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 (INa ). 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 IKr which prolongs the ventricular action potential.
Patients with chronic angina treated with ranolazine in controlled clinical studies had minimal changes in mean heart rate (< 2 bpm) and systolic blood pressure (< 3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients.
Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with ranolazine. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc . At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)].
Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc -concentration relationship of ranolazine.
No proarrhythmic effects were observed on 7-day Holter recordings in 3,162 acute coronary syndrome patients treated with ranolazine. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with ranolazine (80%) versus placebo (87%), including ventricular tachycardia ≥ 3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms.
The pharmacokinetic parameter of ranolazine after single dose administration of 1000 mg ASPRUZYO Sprinkle under fasting conditions are summarized in table 1.
Table 1: Pharmacokinetic parameters of ranolazine after single dose administration of 1000 mg ASPRUZYO Sprinkle under fasting conditions.
10 (2 to 16)
*Median range (min-max) is provided
Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. The pharmacokinetics of the (+) R-and (-) S-enantiomers of ranolazine are similar in healthy volunteers. Steady state is generally achieved within 3 days of twice-daily dosing with ranolazine. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0-T increase slightly more than proportionally to dose, 120% and 140%, 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 and sex.
Absorption and Distribution
After oral administration of ranolazine 1000 mg, median Tmax was 10 hours under fasting conditions and 4.5 to 6 hours under fed. After oral administration of 14 C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from ranolazine granules 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. Over the concentration range of 0.25 to 10 mcg/mL, ranolazine is approximately 62% bound to human plasma proteins.
Compared to the fasted state, the systemic exposure (AUC) increased by 10% and peak drug concentration (Cmax ) increased by 27% when the dose was given 30 minutes after a high fat meal. After administration with a low fat low calorie meal AUC increased by 6% and Cmax increased by 48%.
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. The mean elimination half-lives of ranolazine is approximately 5 hours post single dose ranging from 2 to 11 hours. 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 1000 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 1000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with ranolazine 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.
Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see Contraindications (4)].
Paroxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving ranolazine 1000 mg twice daily. No dose adjustment of ranolazine is required in patients treated with CYP2D6 inhibitors.
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.
The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are increased by 100% in healthy volunteers receiving 80 mg once daily and ranolazine 1000 mg twice daily [see Drug Interactions (7.2)]. Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with ranolazine (1000 mg twice daily) in healthy volunteers. However, in one subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of ranolazine.
The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and ranolazine 1000 mg twice daily.
Ranolazine increases digoxin concentrations by 50% in healthy volunteers receiving ranolazine 1000 mg twice daily and digoxin 0.125 mg once daily [see Drug Interactions (7.2)].
Ranolazine 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan.
In subjects with type 2 diabetes mellitus, the exposure to metformin is increased by 40% and 80% following administration of ranolazine 500 and 1000 mg twice daily, respectively. If co-administered with ranolazine 1000 mg twice daily, do not exceed metformin doses of 1700 mg/day [see Drug Interactions (7.2)].
An in-vitro dissolution study was conducted to evaluate the impact of alcohol on extended-release characteristics of ASPRUZYO Sprinkle. The in-vitro study showed that alcohol causes a rapid release of ranolazine from ASPRUZYO Sprinkle that may increase the risk of adverse events associated with ASPRUZYO Sprinkle. Patients should not consume alcohol when taking ASPRUZYO Sprinkle.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.