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Ranolazine

Medically reviewed by Drugs.com. Last updated on Jun 30, 2020.

Pronunciation

(ra NOE la zeen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Extended Release 12 Hour, Oral:

Ranexa: 500 mg, 1000 mg

Generic: 500 mg, 1000 mg

Brand Names: U.S.

  • Ranexa

Pharmacologic Category

  • Antianginal Agent
  • Cardiovascular Agent, Miscellaneous

Pharmacology

Ranolazine exerts antianginal and anti-ischemic effects without changing hemodynamic parameters (heart rate or blood pressure). At therapeutic levels, ranolazine inhibits the late phase of the inward sodium channel (late INa) in ischemic cardiac myocytes during cardiac repolarization reducing intracellular sodium concentrations and thereby reducing calcium influx via Na+-Ca2+ exchange. Decreased intracellular calcium reduces ventricular tension and myocardial oxygen consumption. It is thought that ranolazine produces myocardial relaxation and reduces anginal symptoms through this mechanism although this is uncertain. At higher concentrations, ranolazine inhibits the rapid delayed rectifier potassium current (IKr) thus prolonging the ventricular action potential duration and subsequent prolongation of the QT interval.

Absorption

Highly variable

Metabolism

Extensive; Hepatic via CYP3A (major) and 2D6 (minor); intestines

Excretion

Primarily urine (75% mostly as metabolites; <5% as unchanged drug); feces (25% mostly as metabolites; <5% as unchanged drug)

Time to Peak

2 to 5 hours

Half-Life Elimination

Ranolazine: Terminal: 7 hours; Metabolites (activity undefined): 6 to 22 hours

Protein Binding

~62%

Special Populations: Renal Function Impairment

Cmax is increased between 40% to 50%.

Special Populations: Hepatic Function Impairment

Cmax is increased by 30% in cirrhotic patients with mild (Child-Pugh class A) hepatic impairment and 80% in cirrhotic patients with moderate (Child-Pugh class B) hepatic impairment.

Use: Labeled Indications

Chronic angina: Treatment of chronic angina

Note: According to the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guidelines for patients with stable ischemic heart disease, ranolazine may be useful when prescribed as a substitute for beta blockers for relief of symptoms if initial treatment with beta blockers leads to unacceptable side effects, is less effective, or if initial treatment with beta-blockers is contraindicated. May also be used in combination with beta-blockers, for relief of symptoms when initial treatment with beta-blockers is not successful (Fihn 2012).

Off Label Uses

Ventricular tachycardia

Data from small prospective studies and retrospective analysis suggest that ranolazine may be beneficial for suppression of ventricular tachycardia [Bunch 2000], [Scirica 2007], [Yeung 2014]. Additional data may be necessary to further define the role of ranolazine in this condition.

Based on the American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death, ranolazine is effective at suppressing ventricular tachycardia.

Contraindications

Hepatic cirrhosis; concurrent strong CYP3A inhibitors; concurrent CYP3A inducers

Dosing: Adult

Note: May be used with beta-blockers, nitrates, calcium channel blockers, antiplatelet therapy, lipid-lowering therapy, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin-receptor blockers.

Chronic angina: Oral: Initial: 500 mg twice daily; may increase to 1,000 mg twice daily as needed (based on symptoms); maximum recommended dose: 1,000 mg twice daily

Ventricular tachycardia (off-label use): Oral: 500 to 1,000 mg every 12 hours (AHA/ACC/HRS [Al-Khatib 2017]; Bunch 2000; Scirica 2007)

Missed doses: If a dose is missed, it should be taken at the next scheduled time; the next dose should not be doubled.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing. Select dose cautiously, starting at the lower end of the dosing range.

Administration

Oral: Administer with or without meals. Swallow tablet whole; do not crush, break, or chew.

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. No alternative formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, close clinical monitoring is advised in the immediate postoperative phase for the theoretical circumstance of reduced absorption after bariatric surgery.

Dietary Considerations

Limit the use of grapefruit juice; the ranolazine dose should not exceed 500 mg twice daily when taken with grapefruit juice or grapefruit-containing products.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Monitor therapy

Angiotensin II Receptor Blockers: Ranolazine may enhance the adverse/toxic effect of Angiotensin II Receptor Blockers. Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Ranolazine may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Monitor therapy

AtorvaSTATin: Ranolazine may increase the serum concentration of AtorvaSTATin. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Avoid combination

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a P-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Ranolazine. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ranolazine. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ranolazine. Management: Limit the ranolazine dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors. Monitor for increased ranolazine effects and toxicities during concomitant use. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ranolazine. Avoid combination

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digitoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digitoxin. Monitor therapy

Digoxin: Ranolazine may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with ranolazine. Reduce digoxin concentrations by either reducing the digoxin dose by 30% to 50% or by modifying the dosing frequency. Consider therapy modification

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: Exceptions to this monograph are discussed in separate Lexi-Interact monographs. Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Lemborexant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lemborexant. Management: The maximum recommended dosage of lemborexant is 5 mg, no more than once per night, when coadministered with weak CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. Consider therapy modification

Lovastatin: Ranolazine may increase the serum concentration of Lovastatin. Ranolazine may also enhance the distribution of lovastatin to specific cells/tissues/organs where P-glycoprotein is present in large amounts (eg, brain, T-lymphocytes, testes, etc.). Management: Monitor closely for signs of lovastatin toxicity (eg, myositis, rhabdomyolysis) with any use of this combination. An American Heart Association scientific statement recommends limiting lovastatin doses to 20 mg daily when used with ranolazine. Monitor therapy

MetFORMIN: Ranolazine may increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Consider therapy modification

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Monitor therapy

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Ranolazine. Monitor therapy

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Avoid combination

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Monitor therapy

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Simvastatin: Ranolazine may increase the serum concentration of Simvastatin. Management: Avoid the concurrent use of ranolazine with simvastatin when possible. If used together, limit simvastatin dose to 20 mg daily and monitor for evidence of simvastatin toxicities (eg, myalgia, liver function test elevations, rhabdomyolysis). Consider therapy modification

Sirolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus. Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Monitor therapy

Thioridazine: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Thioridazine. Management: Consider avoiding concomitant use of thioridazine and weak CYP2D6 inhibitors. If combined, monitor closely for QTc interval prolongation and arrhythmias. Some weak CYP2D6 inhibitors list use with thioridazine as a contraindication. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tolvaptan. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Triazolam: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Triazolam. Management: Consider triazolam dose reduction in patients receiving concomitant weak CYP3A4 inhibitors. Consider therapy modification

Ubrogepant: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Ubrogepant. Management: In patients taking weak CYP3A4 inhibitors, the initial and second dose (given at least 2 hours later if needed) of ubrogepant should be limited to 50 mg. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>0.5% to 10%:

Cardiovascular: Bradycardia (≤4%), hypotension (≤4%), orthostatic hypotension (≤4%), palpitation (≤4%), peripheral edema (≤4%), prolonged QT interval on ECG (>500 msec: ≤1%)

Central nervous system: Dizziness (6%; may be dose-related), headache (≤6%), confusion (≤4%), syncope (≤4%), vertigo (≤4%)

Dermatologic: Hyperhidrosis (≤4%)

Gastrointestinal: Constipation (5%), abdominal pain (≤4%), anorexia (≤4%), dyspepsia (≤4%), nausea (≤4%; dose-related), vomiting (≤4%), xerostomia (≤4%)

Genitourinary: Hematuria (≤4%)

Neuromuscular: Weakness (≤4%)

Ophthalmic: Blurred vision (≤4%)

Otic: Tinnitus (≤4%)

Respiratory: Dyspnea (≤4%)

≤0.5%, postmarketing, and/or case reports: Angioedema, ataxia, decreased glycosylated hemoglobin, decreased T-wave amplitude, dysuria, eosinophilia, hallucination, hypoesthesia, hypoglycemia (diabetic patients), increased blood urea nitrogen, increased serum creatinine, leukopenia, pancytopenia, paresthesia, pruritus, pulmonary fibrosis, renal failure, skin rash, thrombocytopenia, torsade de pointes (Morrow 2007), tremor, T-wave changes (notched), urinary retention, urine discoloration

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: Has been shown to prolong QTc interval in a dose/plasma concentration-related manner. At Tmaxfollowing repeat dosing at 1000 mg twice daily, the mean change in QTc is ~6 msec, but 5% of the population (with the highest plasma concentrations) has at least a 15 msec increase. Cirrhotic patients with mild to moderate hepatic impairment demonstrated a 3-fold increase QT prolongation; use is contraindicated in patients with liver cirrhosis. The incidence of symptomatic arrhythmias was similar to placebo in one trial (Morrow 2007). Risk versus benefit should be assessed in patients maintained on a higher dose (>2,000 mg/day) or exposure, concurrent use of other QT-prolonging drugs, potassium-channel variants known to cause QT prolongation, family history of or congenital long QT syndrome, or known acquired QT interval prolongation.

Disease-related concerns:

• Acute coronary syndrome: Ranolazine will not relieve acute angina episode and has not demonstrated benefit in acute coronary syndrome.

• Hepatic impairment: Ranolazine plasma levels increase by 30% in patients with mild (Child-Pugh class A) and by 80% in patients with moderate (Child-Pugh class B) hepatic impairment. Use is contraindicated in patients with cirrhosis.

• Renal impairment: Acute renal failure has been observed in some patients with severe renal impairment (CrCl <30 mL/minute); if acute renal failure develops (marked increase in serum creatinine associated with increased BUN), discontinue ranolazine and manage appropriately. Monitor renal function periodically in patients with moderate to severe renal impairment; particularly for increases in serum creatinine accompanied by increased BUN. In a renal impairment study, patients with severe impairment exhibited an initial elevation in diastolic blood pressure (~12 to 17 mm Hg at day 3), however, this diminished to ~4 mm Hg increase by day 5 (Jerling 2005); consider monitoring blood pressure in patients with renal dysfunction. Ranolazine has not been evaluated in patients requiring dialysis.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Use is contraindicated with inducers and strong inhibitors of CYP3A.

Special populations:

• Elderly: Use with caution in patients ≥75 years of age; they may experience more adverse events (including serious adverse events) and drug discontinuations due to adverse events.

Monitoring Parameters

Baseline and follow up ECG to evaluate QT interval; monitor renal function periodically in patients with moderate to severe renal impairment, particularly for increases in serum creatinine accompanied by increased BUN; consider monitoring blood pressure in patients with renal dysfunction; correct and maintain serum potassium in normal limits

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

What is this drug used for?

• It is used to treat a type of long-term chest pain (stable angina) in some people.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Dizziness

• Constipation

• Nausea

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.

• Chest pain

• Abnormal heartbeat

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.