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.^{1 2 3 4 6 9 10 11 12 13 14 15 16 18 19 20}

Uses for Ranolazine

Angina

Used in the management of chronic stable angina pectoris.^{1 2 7 12 13 15 16 19}

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.¹

Ranolazine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to meals.¹

Do not break, chew, or crush tablets.¹

Dosage

Adults

Angina

Oral

Initially, 500 mg twice daily; may increase to maximum of 1 g twice daily. ^{1 11 15 16}

Adjustments necessary when used in conjunction with moderate CYP3A inhibitors.¹ (See Interactions).

Prescribing Limits

Adults

Angina

Oral

Maximum 1 g twice daily.¹

Special Populations

Hepatic Impairment

Contraindicated in patients with hepatic cirrhosis.^{1 14 16} (See Contraindications and also see Hepatic Impairment, under Cautions.)

Renal Impairment

No specific dosage recommendations at this time.^{1 5}

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.¹ (See Geriatric Use under Cautions.)

Cautions for Ranolazine

Contraindications

• Hepatic cirrhosis.^{1 10 14 16}

• Concomitant use with potent inhibitors of CYP3A.^{1 10 11 15 16} (See Interactions.)

• Concomitant use with inducers of CYP3A.¹

• Known hypersensitivity to ranolazine or any ingredient in the formulation.⁵

Warnings/Precautions

Prolongation of QT Interval

Has been shown to prolong QT interval corrected for rate (QT_c) in a dose-related manner.^{1 9 12 14 15} In some cases, other drugs that cause QT_c interval prolongation have been associated with torsades de pointes-type arrhythmias and sudden death.¹²

No increased risk of proarrhythmia or sudden death observed in patients with acute coronary syndromes receiving ranolazine.^{1 22}

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

No proarrhythmic effects observed in 7-day Holter monitor recordings in patients with acute coronary syndrome receiving ranolazine.^{1 25} 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.^{1 25}

Specific Populations

Pregnancy

Category C.¹

Lactation

Not known whether ranolazine is distributed into milk; discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 5}

Geriatric Use

No substantial differences in safety or efficacy observed in patients ≥65 years of age relative to younger adults.¹ However, greater severity of adverse effects and increased incidence of drug discontinuance observed in patients ≥75 years of age.¹

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.¹

Hepatic Impairment

Increased plasma concentrations and increased QT_c-prolonging effect in patients with mild or moderate hepatic impairment.^{1 5} Contraindicated in patients with hepatic cirrhosis.^{1 16} (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.^{6 11}

Safety and efficacy not established in patients undergoing dialysis.^{1 5}

Gender

Magnitude of the treatment effect and improvements in exercise tolerance are smaller in women than in men.^{1 5} No dosage adjustment required.¹

Common Adverse Effects

Constipation,¹ dizziness,¹ nausea,¹ headache.¹

Drug Interactions

Metabolized by CYP isoenzymes, principally CYP3A and, to a lesser extent, CYP2D6.^{1 6 9 10 11 15 16 19 20} Weak inhibitor of CYP isoenzyme 3A and moderate inhibitor of CYP isoenzyme 2D6.^{1 11 16} Does not inhibit CYP isoenzymes 1A2, 2C8, 2C9, 2C19, or 2E1.^{1 24}

Substrate and moderate inhibitor of the p-glycoprotein transport system.^{1 11 16}

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A and 2D6 inhibitors: Potential pharmacokinetic interaction (increased plasma ranolazine concentrations).¹ Avoid concomitant use with potent CYP3A inhibitors.¹ Maximum ranolazine dosage of 500 mg twice daily in patients receiving moderate CYP3A inhibitors (see Specific Drugs and Foods under Interactions).¹

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A and 2D6 substrates: Potential pharmacokinetic interaction (increased plasma concentration of substrate).¹

Drugs that Inhibit the p-Glycoprotein Transport System

Potential pharmacokinetic interaction (increased absorption of ranolazine) with p-glycoprotein inhibitors.^{1 11 16 19} Reduce dosage of ranolazine as needed based on clinical response in patients receiving p-glycoprotein inhibitors (see Specific Drugs and Foods under Interactions).¹

Drugs That Prolong QT Interval

Potential pharmacologic effect (additive effect on QT interval prolongation).¹¹ Experience with concomitant use of ranolazine with drugs that prolong the QT interval is limited.¹

Specific Drugs and Foods

Ranolazine Pharmacokinetics

Absorption

Bioavailability

Following oral administration, bioavailability is approximately 55%. ¹

Peak plasma concentrations occur between 2–5 hours. ¹ Steady state generally reached within 3 days following twice-daily dosing.¹

Food

Food does not appear to affect absorption.¹

Plasma Concentrations

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

Special Populations

In patients with mild, moderate, or severe renal impairment, plasma concentrations increased by 40–50%; increased exposure independent of degree of impairment.¹

In patients with mild or moderate hepatic impairment, plasma concentrations increased by factors of 1.3 or 1.8, respectively. ¹

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 QT_c interval.¹

Distribution

Plasma Protein Binding

Approximately 62%.¹

Elimination

Metabolism

Extensively metabolized in liver and intestine by CYP3A4 and CYP2D6. ¹ (See Interactions.)

Elimination Route

Excreted in urine (75%) mainly as metabolites and in feces (25%).¹

Half-life

Terminal half-life is approximately 7 hours.¹

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹

Actions

• Exact mechanism of antianginal action not fully elucidated; may involve the shifting of adenosine triphosphate (ATP) production away from fatty acid oxidation (i.e., partial inhibition of fatty acid oxidation) in favor of more oxygen-efficient glucose oxidation, especially when free fatty acid concentrations are elevated (e.g., during ischemia), leading to reduced oxygen demand and symptoms of ischemia without affecting cardiac work.^{1 2 3 4 9 10 11 14 15 17 18}

• May decrease the magnitude of the late (i.e., sustained, persistent) sodium current¹ resulting in a net reduction in intracellular sodium concentrations, reversal of calcium overload, restoration of ventricular pump function, and prevention of ischemia-induced arrhythmias.^{10 11 12 13 15 16 17 18 19}

• Effects not dependent upon reductions in heart rate or BP.^{1 2 3 7 9 10 12 13 14 15 16 17 20}

• Prolongation of QT interval secondary to inhibition of I_Kr, which prolongs the ventricular action potential.¹

Advice to Patients

• Risk of changes in ECG (i.e., prolongation of QT interval corrected for rate [QT_c]).¹

• Importance of informing clinicians of any personal or family history of QT_c interval prolongation or congenital long QT syndrome.¹

• Importance of informing clinicians if patient is receiving drugs that prolong the QT_c interval (e.g., class Ia [e.g., quinidine] or III [e.g., dofetilide, sotalol] antiarrhythmic agents, erythromycin, antipsychotic agents [e.g., thioridazine, ziprasidone]).¹

• Importance of advising patients that ranolazine should be avoided in patients receiving drugs that are potent inhibitors of CYP3A (e.g., clarithromycin, ketoconazole, nefazodone, ritonavir).¹

• Risk of dizziness and lightheadedness; avoid driving, operating machinery, or engaging in other activities requiring mental alertness or coordination while taking ranolazine until gain experience with the drug’s effects.¹

• Importance of advising patients that ranolazine should be avoided in patients receiving drugs that are inducers of CYP3A (e.g., barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, rifapentine, St. John’s wort).¹

• Importance of informing clinicians if patient is receiving drugs that are moderate inhibitors of CYP3A (e.g., diltiazem, erythromycin, verapamil) or inhibitors of P-glycoprotein (e.g., cyclosporine).¹

• Importance of informing patients that ranolazine dosages exceeding 1 g twice daily should not be used.¹

• Importance of advising patients to swallow tablets whole and not to break, chew, or crush the tablets.¹

• Importance of informing patients that ranolazine may be taken without regard to meals.¹

• Importance of advising patients that if a dose is missed, next dose should be taken at regularly scheduled time; dose should not be doubled.¹

• Importance of informing patients that ranolazine will not abate an acute episode of angina.¹

• Importance of informing patients that ranolazine should not be used in patients with hepatic cirrhosis.¹

• Importance of informing clinicians if fainting spells occur.¹

• Importance of informing clinicians if swelling of the eyes, face, lips, tongue, or throat occurs.¹

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., cardiovascular disease).¹ Importance of limiting grapefruit juice and grapefruit-containing products.¹

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

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.

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