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Ranolazine

Pronunciation

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
Brands: Ranexa

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

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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 (QTc) in a dose-related manner.1 9 12 14 15 In some cases, other drugs that cause QTc 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 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.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 QTc-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

Interactions for Ranolazine

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

Drug or Food

Interaction

Comments

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

Additive effects on prolongation of QT interval10 16

Experience with concomitant use limited1

Antidepressants, tricyclic

Possible decreased metabolism of tricyclic antidepressants1

Consider reducing tricyclic antidepressant dosage if used concomitantly 1

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

Increased plasma ranolazine concentrations1 9 10 11 15 19 20

Concomitant use with itraconazole or ketoconazole contraindicated1 10 15 16

Maximum ranolazine dosage of 500 mg twice daily in patients receiving fluconazole1

Antipsychotics (e.g., thioridazine, ziprasidone)

Additive effects on prolongation of QT interval10 16

Possible decreased metabolism of antipsychotics1

Experience with concomitant use limited1

Consider reducing antipsychotic dosage if used concomitantly 1

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

Decreased plasma ranolazine concentrations1

Avoid concomitant use1

Calcium-channel blocking agents (diltiazem, verapamil)

Increased plasma ranolazine concentrations1 9 10 11 15 19 20

Maximum ranolazine dosage of 500 mg twice daily in patients receiving diltiazem or verapamil1

Carbamazepine

Potential decrease in plasma ranolazine concentrations1

Avoid concomitant use1

Cimetidine

Pharmacokinetic interactions unlikely1

No dosage adjustment required1

Cyclosporine

Increased absorption of ranolazine1 11 16 19

Potential increase in plasma cyclosporine concentrations1

Reduce ranolazine dosage as needed based on clinical response1

Dosage adjustment of cyclosporine may be required1

Dextromethorphan

Formation of dextrorphan, the main metabolite of dextromethorphan, partially inhibited by ranolazine in extensive metabolizers of dextromethorphan1

Digoxin

Increased plasma digoxin concentrations;1 9 10 11 15 16 19 no effect on plasma ranolazine concentrations1

Reduced digoxin dosage may be necessary1 10 19

Grapefruit juice

Potential increase in plasma ranolazine concentrations1

Maximum ranolazine dosage of 500 mg twice daily in patients consuming grapefruit juice or grapefruit products during therapy1

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

Increased plasma ranolazine concentrations1 15 19 20

Concomitant use contraindicated1 11 15 16

Lovastatin

Potential increase in plasma lovastatin concentrations1

Dosage adjustment of lovastatin may be required1

Macrolides (e.g., erythromycin, clarithromycin)

Increased plasma ranolazine concentrations1 15 20

Concomitant use with clarithromycin contraindicated1 11 15 16

Maximum ranolazine dosage of 500 mg twice daily in patients receiving erythromycin1

Metoprolol

Increased plasma metoprolol concentrations1

Dosage adjustment of metoprolol not required1

Paroxetine

Increased plasma ranolazine concentrations1 10 11 19

Dosage adjustment of ranolazine not required1 10 19

Simvastatin

Increased plasma simvastatin concentrations; no effect on ranolazine concentrations1 10 11 15 16 20

Limit simvastatin dosage to 20 mg daily in patients receiving ranolazine1

Dosage adjustment of ranolazine not required1

Sirolimus

Potential increase in plasma sirolimus concentrations1

Dosage adjustment of sirolimus may be required1

Tacrolimus

Potential increase in plasma tacrolimus concentrations1

Dosage adjustment of tacrolimus may be required1

St. John’s Wort

Potential decrease in plasma ranolazine concentrations1

Avoid concomitant use1

Warfarin

Pharmacokinetic interactions unlikely11 19

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 QTc 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 QTc 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 IKr, which prolongs the ventricular action potential.1

Advice to Patients

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

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

  • Importance of informing clinicians if patient is receiving drugs that prolong the QTc 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.

Ranolazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

500 mg

Ranexa

Gilead Sciences

1000 mg

Ranexa

Gilead Sciences

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Ranexa 1000MG 12-hr Tablets (GILEAD SCIENCES): 60/$391.00 or 180/$1,144.99

Ranexa 500MG 12-hr Tablets (GILEAD SCIENCES): 60/$249.99 or 180/$715.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 20, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Gilead Sciences, Inc. Ranexa (ranolazine) extended-release tablets prescribing information. Foster City, CA; 2011 Jul. Available at . Accessed 2011 Aug 28.

2. Chaitman BR, Pepine CJ, Parker JO et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004; 291:309-16. [PubMed 14734593]

3. Gaffney SM. Ranolazine, a novel agent for chronic stable angina. Pharmacotherapy. 2006; 26:135-42. [PubMed 16506355]

4. Chaitman BR, Skettino SL, Parker JO et al. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004; 43:1375-82. [PubMed 15093870]

5. CV Therapeutics, Inc., Palo Alto, CA: Personal communication.

6. Jerling M, Abdallah H. Effect of renal impairment on multiple-dose pharmacokinetics of extended-release ranolazine. Clin Pharmacol Ther. 2005; 78:288-97. [PubMed 16153399]

7. Stone PH, Gratsiansky NA, Blokhin A, et al, for the ERICA Investigators. Anti-anginal efficacy of ranolazine when added to maximal therapy with conventional therapy: The efficacy of ranolazine in chronic angina trial. Abstract presented at American Heart Association Scientific Sessions 2005. Dallas, TX, 2005, Nov 13-16. Abstract No. 3491.

8. Suckow MA, Gutierrez LS, Risatti CA et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC(Min/+) mice. Cancer Lett. 2004; 209:165-9. [PubMed 15159018]

9. Anderson JR, Nawarskas JJ. Ranolazine: a metabolic modulator for the treatment of chronic stable angina. Cardiol Rev. 2005 Jul-Aug; 13:202-10.

10. Zerumsky K, McBride BF. Ranolazine in the management of chronic stable angina. Am J Health Syst Pharm. 2006; 63:2331-8. [PubMed 17106005]

11. Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006; 113:2462-72. [PubMed 16717165]

12. Abrams J, Jones CA, Kirkpatrick P. Ranolazine. Nat Rev Drug Discov. 2006; 5:453-4. [PubMed 16821287]

13. Stone PH, Gratsiansky NA, Blokhin A et al. Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol. 2006; 48:566-75. [PubMed 16875985]

14. Cairns JA. Ranolazine: augmenting the antianginal armamentarium. J Am Coll Cardiol. 2006; 48:576-8. [PubMed 16875986]

15. Siddiqui MA, Keam SJ. Ranolazine: a review of its use in chronic stable angina pectoris. Drugs. 2006; 66:693-710. [PubMed 16620147]

16. Anon. Ranolazine (Ranexa) for chronic angina. Med Lett Drugs Ther. 2006; 48:46-7. [PubMed 16770296]

17. Belardinelli L, Shryock JC, Fraser H. Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine. Heart. 2006; 92 Suppl 4:iv6-14. [PubMed 16775092]

18. Makielski JC, Valdivia CR. Ranolazine and late cardiac sodium current--a therapeutic target for angina, arrhythmia and more?. Br J Pharmacol. 2006; 148:4-6. [PubMed 16520741]

19. Jerling M. Clinical pharmacokinetics of ranolazine. Clin Pharmacokinet. 2006; 45:469-91. [PubMed 16640453]

20. Jerling M, Huan BL, Leung K et al. Studies to investigate the pharmacokinetic interactions between ranolazine and ketoconazole, diltiazem, or simvastatin during combined administration in healthy subjects. J Clin Pharmacol. 2005; 45:422-33. [PubMed 15778423]

21. Pfizer. Norvasc (amlodipine besylate) tablets prescribing information. New York, NY; 2005 Sep.

22. Morrow DA, Scirica BM, Karwatowska-Prokopczuk E et al. Effects of ranolazine on recurrent cardiovascular events in patients with non-ST-elevation acute coronary syndromes: the MERLIN-TIMI 36 randomized trial. JAMA. 2007; 297:1775-83. [PubMed 17456819]

23. Morrow DA, Scirica BM, Chaitman BR et al. Evaluation of the glycometabolic effects of ranolazine in patients with and without diabetes mellitus in the MERLIN-TIMI 36 randomized controlled trial. Circulation. 2009; 119:2032-9. [PubMed 19349325]

24. Gilead Sciences, Inc., Ranexa (ranolazine) extended-release tablets prescribing information. Foster City, CA; 2010 Sep.

25. Scirica BM, Morrow DA, Hanoch H et al. Effect of ranolazine, an antianginal agent with novel electrophysiological properties, on the incidence of arrhythmias in patients with non ST-segment elevation acute coronary syndrome: results from the metabolic efficiency with ranolazine for less ischemia in non ST-elevation acute coronary syndrome thrombolysis in myocardial infarction 36 (MERLIN-TIMI 36) randomized controlled trial. Circulation. 2007; 116:1647-52. [PubMed 17804441]

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