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Ranolazine

Pronunciation

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

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).

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.

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.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, plasma ranolazine levels increased ~40% to 50% in patients with varying degrees of renal dysfunction. Discontinue if acute renal failure develops during treatment. Ranolazine has not been evaluated in patients requiring dialysis, although it is unlikely to be removed by hemodialysis due to plasma protein binding.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. Use is contraindicated with hepatic cirrhosis.

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: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

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

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

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

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. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. 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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Digoxin: Ranolazine may increase the serum concentration of Digoxin. 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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Consider therapy modification

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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

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 (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

MetFORMIN: Ranolazine may increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. 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

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). 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

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

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. 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. 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

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. 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: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. 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% (Limited to important or life-threatening): Angioedema, 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, 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

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, constipation, or dyspepsia. Have patient report immediately to prescriber signs of renal impairment, severe dizziness, syncope, blurred vision, angina, illogical thinking, bradycardia, arrhythmia, dyspnea, or edema of extremities (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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