Skip to main content

Ranolazine (Monograph)

Brand name: Ranexa
Drug class: Cardiac Drugs, Miscellaneous
VA class: CV250
Chemical name: N-(2,6-Dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazineacetamide
Molecular formula: C24H33N3O4
CAS number: 95636-55-5

Medically reviewed by Drugs.com on Jan 10, 2024. Written by ASHP.

Introduction

Antianginal agent; a piperazine derivative.

Uses for Ranolazine

Angina

Used in the management of chronic stable angina pectoris.

May be used in combination with β-adrenergic blocking agents, calcium channel blocking agents, nitrates, antiplatelet therapy, lipid-lowering therapy, ACE inhibitors, or angiotensin receptor blocking agents.

Ranolazine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.

Do not break, chew, or crush tablets.

Dosage

Adults

Angina
Oral

Initially, 500 mg twice daily; may increase to maximum of 1 g twice daily.

Adjustments necessary when used in conjunction with moderate CYP3A inhibitors. (See Interactions).

Prescribing Limits

Adults

Angina
Oral

Maximum 1 g twice daily.

Special Populations

Hepatic Impairment

Contraindicated in patients with hepatic cirrhosis. (See Contraindications and also see Hepatic Impairment, under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Patients

Select dosage with caution, usually initiating therapy at the low end of the dosage range because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy. (See Geriatric Use under Cautions.)

Cautions for Ranolazine

Contraindications

Warnings/Precautions

Prolongation of QT Interval

Has been shown to prolong QT interval corrected for rate (QTc) in a dose-related manner. In some cases, other drugs that cause QTc interval prolongation have been associated with torsades de pointes-type arrhythmias and sudden death.

No increased risk of proarrhythmia or sudden death observed in patients with acute coronary syndromes receiving ranolazine.

Experience with high ranolazine dosages (>1 g twice daily) or exposure, other QTc interval-prolonging drugs, potassium channel variants resulting in a long QTc interval, or in patients with a family history of long QTc syndrome or with known acquired or congenital QTc interval prolongation, is limited. (See Interactions.) Dosages >1 g twice daily should not be used.

No proarrhythmic effects observed in 7-day Holter monitor recordings in patients with acute coronary syndrome receiving ranolazine. Ranolazine was associated with a lower incidence of arrhythmias (bradycardia, new atrial fibrillation, supraventricular tachycardia, ventricular tachycardia lasting ≥8 beats) compared with placebo; however, no reduction in mortality, hospitalization secondary to arrhythmia, or arrhythmia symptoms observed.

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether ranolazine is distributed into milk; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

No substantial differences in safety or efficacy observed in patients ≥65 years of age relative to younger adults. However, greater severity of adverse effects and increased incidence of drug discontinuance observed in patients ≥75 years of age.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Increased plasma concentrations and increased QTc-prolonging effect in patients with mild or moderate hepatic impairment. Contraindicated in patients with hepatic cirrhosis. (See Prolongation of QT Interval under Cautions.)

Renal Impairment

BP increases (≤15 mm Hg) observed in patients with severe renal impairment; monitor BP periodically in such patients.

Safety and efficacy not established in patients undergoing dialysis.

Gender

Magnitude of the treatment effect and improvements in exercise tolerance are smaller in women than in men. No dosage adjustment required.

Common Adverse Effects

Constipation, dizziness, nausea, headache.

Drug Interactions

Metabolized by CYP isoenzymes, principally CYP3A and, to a lesser extent, CYP2D6. Weak inhibitor of CYP isoenzyme 3A and moderate inhibitor of CYP isoenzyme 2D6. Does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2E1.

Substrate and moderate inhibitor of the p-glycoprotein transport system.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A and 2D6 inhibitors: Potential pharmacokinetic interaction (increased plasma ranolazine concentrations). Avoid concomitant use with potent CYP3A inhibitors. Maximum ranolazine dosage of 500 mg twice daily in patients receiving moderate CYP3A inhibitors (see Specific Drugs and Foods under Interactions).

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A and 2D6 substrates: Potential pharmacokinetic interaction (increased plasma concentration of substrate).

Drugs that Inhibit the p-Glycoprotein Transport System

Potential pharmacokinetic interaction (increased absorption of ranolazine) with p-glycoprotein inhibitors. Reduce dosage of ranolazine as needed based on clinical response in patients receiving p-glycoprotein inhibitors (see Specific Drugs and Foods under Interactions).

Drugs That Prolong QT Interval

Potential pharmacologic effect (additive effect on QT interval prolongation). Experience with concomitant use of ranolazine with drugs that prolong the QT interval is limited.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antiarrhythmic agents (e.g., dofetilide, quinidine, sotalol)

Additive effects on prolongation of QT interval

Experience with concomitant use limited

Antidepressants, tricyclic

Possible decreased metabolism of tricyclic antidepressants

Consider reducing tricyclic antidepressant dosage if used concomitantly

Antifungals, azole (e.g., fluconazole, itraconazole, ketoconazole)

Increased plasma ranolazine concentrations

Concomitant use with itraconazole or ketoconazole contraindicated

Maximum ranolazine dosage of 500 mg twice daily in patients receiving fluconazole

Antipsychotics (e.g., thioridazine, ziprasidone)

Additive effects on prolongation of QT interval

Possible decreased metabolism of antipsychotics

Experience with concomitant use limited

Consider reducing antipsychotic dosage if used concomitantly

Antituberculosis agents (e.g., rifabutin, rifampin, rifapentine)

Decreased plasma ranolazine concentrations

Avoid concomitant use

Calcium-channel blocking agents (diltiazem, verapamil)

Increased plasma ranolazine concentrations

Maximum ranolazine dosage of 500 mg twice daily in patients receiving diltiazem or verapamil

Carbamazepine

Potential decrease in plasma ranolazine concentrations

Avoid concomitant use

Cimetidine

Pharmacokinetic interactions unlikely

No dosage adjustment required

Cyclosporine

Increased absorption of ranolazine

Potential increase in plasma cyclosporine concentrations

Reduce ranolazine dosage as needed based on clinical response

Dosage adjustment of cyclosporine may be required

Dextromethorphan

Formation of dextrorphan, the main metabolite of dextromethorphan, partially inhibited by ranolazine in extensive metabolizers of dextromethorphan

Digoxin

Increased plasma digoxin concentrations; no effect on plasma ranolazine concentrations

Reduced digoxin dosage may be necessary

Grapefruit juice

Potential increase in plasma ranolazine concentrations

Maximum ranolazine dosage of 500 mg twice daily in patients consuming grapefruit juice or grapefruit products during therapy

HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, saquinavir)

Increased plasma ranolazine concentrations

Concomitant use contraindicated

Lovastatin

Potential increase in plasma lovastatin concentrations

Dosage adjustment of lovastatin may be required

Macrolides (e.g., erythromycin, clarithromycin)

Increased plasma ranolazine concentrations

Concomitant use with clarithromycin contraindicated

Maximum ranolazine dosage of 500 mg twice daily in patients receiving erythromycin

Metoprolol

Increased plasma metoprolol concentrations

Dosage adjustment of metoprolol not required

Paroxetine

Increased plasma ranolazine concentrations

Dosage adjustment of ranolazine not required

Simvastatin

Increased plasma simvastatin concentrations; no effect on ranolazine concentrations

Limit simvastatin dosage to 20 mg daily in patients receiving ranolazine

Dosage adjustment of ranolazine not required

Sirolimus

Potential increase in plasma sirolimus concentrations

Dosage adjustment of sirolimus may be required

Tacrolimus

Potential increase in plasma tacrolimus concentrations

Dosage adjustment of tacrolimus may be required

St. John’s Wort

Potential decrease in plasma ranolazine concentrations

Avoid concomitant use

Warfarin

Pharmacokinetic interactions unlikely

Ranolazine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, bioavailability is approximately 55%.

Peak plasma concentrations occur between 2–5 hours. Steady state generally reached within 3 days following twice-daily dosing.

Food

Food does not appear to affect absorption.

Plasma Concentrations

QT interval increases with plasma ranolazine concentrations. Relationship between plasma ranolazine concentrations and QTc is linear over a concentration range up to several times greater than the concentrations produced by a dosage of 1 g twice daily.

Special Populations

In patients with mild, moderate, or severe renal impairment, plasma concentrations increased by 40–50%; increased exposure independent of degree of impairment.

In patients with mild or moderate hepatic impairment, plasma concentrations increased by factors of 1.3 or 1.8, respectively.

Age, weight, gender, race, heart rate, NYHA class I to IV heart failure, and diabetes have no substantial effect on the relationship between plasma ranolazine concentrations and increases in QTc interval.

Distribution

Plasma Protein Binding

Approximately 62%.

Elimination

Metabolism

Extensively metabolized in liver and intestine by CYP3A4 and CYP2D6. (See Interactions.)

Elimination Route

Excreted in urine (75%) mainly as metabolites and in feces (25%).

Half-life

Terminal half-life is approximately 7 hours.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Ranolazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

500 mg

Ranexa

Gilead Sciences

1000 mg

Ranexa

Gilead Sciences

AHFS DI Essentials™. © Copyright 2024, Selected Revisions January 20, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

Reload page with references included