Ranexa

Generic Name: Ranolazine
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

Introduction

Antianginal agent; a piperazine derivative.^{1 2 3 4 6 9 10 11 12 13 14 15 16 18 19 20}

Uses for Ranexa

Angina

Used in combination with amlodipine besylate, β-adrenergic blocking agents, or nitrates in the management of chronic stable angina pectoris.^{1 2 7 12 13 15 16 19}

Not indicated as first-line antianginal therapy because of risk of QT interval prologation; reserve for patients who do not respond to other antianginal agents.^{1 12 15 16 19} (See Contraindications and also Prolongation of QT Interval under Cautions.)

Ranexa 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}

Prescribing Limits

Adults

Angina

Oral

Maximum 1 g twice daily.¹

Special Populations

Hepatic Impairment

Contraindicated.^{1 14 16} (See Contraindications and also 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 Ranexa

Contraindications

• 
  

  Mild, moderate, or severe (Child-Pugh class A, B, or C, respectively) hepatic impairment.^{1 10 14 16}

  
  


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  Preexisting QT interval prolongation. ^{1 10 15 16} (See Prolongation of QT Interval under Cautions.)

  
  


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  Concomitant therapy with drugs known to prolong QT interval. ^{1 10 15 16} (See Prolongation of QT Interval under Cautions and see Specific Drugs and Foods under Interactions.)

  
  


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  Concomitant use with potent or moderately potent inhibitors of CYP3A (e.g., diltiazem).^{1 10 11 15 16} (See Interactions.)

  
  


• 
  

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

  
  

Warnings/Precautions

Warnings

Prolongation of QT Interval

Dose-related QT_c interval prolongation has occured;^{1 9 12 14 15} may be associated with torsades de pointes-type arrhythmias and sudden death.^{1 12}

Perform ECG evaluations before and periodically during therapy to monitor for effects on the QT interval.^{1 5 11}

Dosages >1 g twice daily should not be used.¹

Avoid use in patients with preexisting QT interval prolongation (e.g., congenital long QT syndrome, uncorrected hypokalemia) or known history of ventricular tachycardia, and in patients receiving drugs that prolong the QT interval (e.g., class Ia [e.g., quinidine] or III [e.g., dofetilide, sotalol] antiarrhythmic agents, antipsychotic agents [e.g., thioridazine, ziprasidone]).^{1 10 15 16} (See Specific Drugs and Foods under Interactions.)

Carcinogenicity

Tumor formation and malignancy reported in mice; clinical importance not established.^{1 8}

General Precautions

Hematologic Effects

Small decreases in hematocrit reported; no evidence of occult fecal blood loss.¹

Transient eosinophilia reported rarely.¹

Renal Effects

Possible increased S_cr.¹ Elevations of S_cr appear to have a rapid onset, do not progress during long-term therapy, and are reversible following discontinuance of therapy.¹

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 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 mild, moderate, or severe hepatic impairment.^{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.^{1 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 Ranexa

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

Substrate and 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

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}

Drugs That Prolong QT Interval

Potential pharmacologic effect (additive effect on QT interval prolongation).^{1 11} (See Contraindications under Cautions.)

Specific Drugs and Foods

Drug or Food	Interaction	Comments
Antiarrhythmic agents (e.g., dofetilide, quinidine, sotalol)	Additive effects on prolongation of QT interval1 10 16	Concomitant use contraindicated1 10 15 16
Antidepressants, tricyclic	Possible decreased metabolism of tricyclic antidepressants1	Consider reducing tricyclic antidepressant dosage if used concomitantly 1
Antifungals, azole (e.g., itraconazole, ketoconazole)	Increased plasma ranolazine concentrations; increased risk of prolongation of QT interval1 9 10 11 15 19 20	Concomitant use contraindicated1 10 15 16
Antipsychotics (e.g., thioridazine, ziprasidone)	Additive effects on prolongation of QT interval1 10 16	Concomitant use contraindicated1 10 16
Calcium-channel blocking agents (diltiazem, verapamil)	Increased plasma ranolazine concentrations; increased risk of prolongation of QT interval1 9 10 11 15 19 20	Concomitant use contraindicated1 10 16
Cimetidine	Pharmacokinetic interactions unlikely1	No dosage adjustment required1
Cyclosporine	Increased absorption of ranolazine1 11 16 19	Use concomitantly with caution1
Digoxin	Possible increased plasma digoxin concentrations;1 9 10 11 15 16 19 no effect on plasma ranolazine concentrations1	Reduced digoxin dosage may be necessary;1 10 19 dosage adjustment of ranolazine not required1
Grapefuit juice	Potential increase in plasma ranolazine concentrations1	Avoid grapefruit juice or grapefruit products during therapy1 11 16
HIV protease inhibitors (e.g., ritonavir)	Increased plasma ranolazine concentrations; increased risk of prolongation of QT interval1 15 19 20	Concomitant use contraindicated1 11 15 16
Macrolides (e.g., erythromycin, clarithromycin)	Increased plasma ranolazine concentrations1 15 20	Concomitant use contraindicated1 11 15 16
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	Consider reducing simvastatin dosage if used concomitantly; dosage adjustment of ranolazine not required1
Warfarin	Pharmacokinetic interactions unlikely1 11 19

Ranexa 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 fourfold greater than the concentrations produced by a dosage of 1 g twice daily.¹

Special Populations

In patients with renal impairment, plasma concentrations increased by 50%.¹

In patients with mild or moderate hepatic impairment, plasma concentrations increased by factors of 1.3 or 1.6, respectively. ¹

Age, weight, gender, race, heart rate, NYHA class I to IV CHF, 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

ActionsActions

• 
  

  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 current 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}

  
  

Advice to Patients

• 
  

  Importance of taking only as prescribed; necessity of ECG monitoring before and during therapy.¹

  
  


• 
  

  Importance of advising patients to swallow tablets whole and not to break, chew, or crush the tablets.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 clinicians if palpitations or fainting spells occur.¹

  
  


• 
  

  Risk of dizziness and lightheadedness; avoid driving, operating machinery, or engaging in other activities requiring mental alertness or coordination until effects on individual are known.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 avoiding grapefruit juice.¹

  
  


• 
  

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. 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/$367.99 or 180/$1076.93

Ranexa 500MG 12-hr Tablets (GILEAD SCIENCES): 60/$253.99 or 180/$694

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions September 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. CV Therapeutics, Inc. Ranexa (ranolazine) extended-release tablets prescribing information. Palo Alto, CA; 2006 Feb.

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.

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