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Ranolazine

Medically reviewed by Drugs.com. Last updated on Jun 8, 2019.

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

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

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

Dosage adjustment for ranolazine with concomitant medications:

Diltiazem, erythromycin, fluconazole, verapamil, and other moderate CYP3A inhibitors: Ranolazine dose should not exceed 500 mg twice daily

CYP3A inducers or strong CYP3A inhibitors: Concomitant use is contraindicated

P-glycoprotein inhibitors (eg, cyclosporine): Titrate ranolazine based on clinical response

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.

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

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

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

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Ranolazine. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Exceptions: Fluconazole; Isavuconazonium Sulfate. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. 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 the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May increase the serum concentration of Ranolazine. Management: Limit ranolazine dose to a maximum of 500 mg twice daily when used with diltiazem or verapamil. Exceptions: Bepridil. Consider therapy modification

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-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

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

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 adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). 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. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

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

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

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). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

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

Erdafitinib: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. 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

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

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

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 enhance the myopathic (rhabdomyolysis) effect of 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.). 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

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

Perhexiline: CYP2D6 Inhibitors (Weak) may increase the serum concentration of Perhexiline. Monitor therapy

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

P-glycoprotein/ABCB1 Substrates: Ranolazine may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

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

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

RifAMPin: May decrease the serum concentration of Ranolazine. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. 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, avoid doses of simvastatin greater than 20 mg/day. Consider therapy modification

St John's Wort: May decrease the serum concentration of Ranolazine. Avoid combination

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): Ranolazine may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

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

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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. 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.

Frequently reported side effects of this drug

• Headache

• Dizziness

• Constipation

• Nausea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Kidney problems like urinary retention, hematuria, change in amount of urine passed, or weight gain.

• Chest pain

• Abnormal heartbeat

• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of 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 brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Further information

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

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