OVERVIEW

CASE REPORT

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Ranolazine	95635-55-5	C24-H33-N3-O4

ANNOTATED BIBLIOGRAPHY

References updated: 20 May 2018

• Zimmerman HJ. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 639-71.

  (Expert review of hepatotoxicity published in 1999 before the availability of ranolazine).
• De Marzio DH, Navarro VJ. Hepatotoxicity of cardiovascular and antidiabetic drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 519-40.

  (Review of hepatotoxicity of cardiovascular drugs; ranolazine is not discussed).
• Michel T, Hoffman BB. Treatment of myocardial ischemia and hypertension. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 745-88.

  (Textbook of pharmacology and therapeutics).
• Thadani U, Ezekowitz M, Fenney L, Chiang YK. Double-blind efficacy and safety study of a novel anti-ischemic agent, ranolazine, versus placebo in patients with chronic stable angina pectoris. Ranolazine Study Group. Circulation 1994; 90: 726-34. [PubMed: 8044941]

  (Among 318 patients with angina pectoris treated with intermediate release ranolazine [30, 60 or 120 mg] or placebo 3 times daily for 4 weeks, exercise tolerance was not different in the 4 groups and side effects included headaches, dizziness and fatigue while differences in laboratory tests were not “clinically significant”).
• Pepine CJ, Wolff AA. A controlled trial with a novel anti-ischemic agent, ranolazine, in chronic stable angina pectoris that is responsive to conventional antianginal agents. Ranolazine Study Group. Am J Cardiol. 1999; 84: 46-50. [PubMed: 10404850]

  (Among 312 patients with angina pectoris treated with intermediate release ranolazine [600, 800 or 1200 mg daily] or placebo, exercise tolerance improved compared to placebo at peak plasma levels and the only side effects were mild gastrointestinal upset; there were “no significant changes in…clinical laboratory blood tests”).
• Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, Wang W, et al.; Combination Assessment of Ranolazine In Stable Angina (CARISA) Investigators. 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]

  (Among 823 patients with symptomatic angina despite antianginal medications who were treated with ranolazine [750 or 100 mg] or placebo twice daily for 12 weeks, exercise tolerance was increased with ranolazine; the most common side effects were constipation, dizziness, nausea and fatigue; no mention of ALT changes or hepatotoxicity).
• Chaitman BR. Efficacy and safety of a metabolic modulator drug in chronic stable angina: review of evidence from clinical trials. J Cardiovasc Pharmacol Ther 2004; 9 Suppl 1: S47-64. [PubMed: 15378131]

  (Review of the efficacy and safety of sustained release ranolazine which results in significant improvement in angina and has modest side effects such as fatigue, dizziness, nausea and constipation and rarely syncope; “ranolazine does not cause deleterious changes in laboratory parameters”).
• Ranolazine (ranexa) for chronic angina. Med Lett Drugs Ther 2006; 48 (1236): 46-7. [PubMed: 16770296]

  (Concise review of pharmacology, clinical efficacy, safety and costs of ranolazine shortly after its approval in the US; mentions side effects of constipation, nausea, dizziness and headache, but does not mention ALT elevations or hepatotoxicity).
• Koren MJ, Crager MR, Sweeney M. Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol 2007; 49: 1027-34. [PubMed: 17349881]

  (Among 746 patients with chronic angina treated with ranolazine [500 to 1000 mg twice daily] in an open label extension study for an average of 2.8 years, the drug was well tolerated and there was no mention of ALT elevations or clinically apparent liver injury).
• Morrow DA, Scirica BM, Karwatowska-Prokopczuk E, Murphy SA, Budaj A, Varshavsky S, Wolff AA, et al.; MERLIN-TIMI 36 Trial Investigators. 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]

  (Among 6580 patients with acute coronary syndrome treated with ranolazine [1000 mg twice daily] or placebo, there were no differences in acute or one year mortality and adverse events included dizziness [13% vs 7%], nausea [9% vs 6%], constipation [9% vs 3%] and syncope [3.3% vs 2.3%]; no mention of ALT elevations or hepatotoxicity).
• Miles RH, Passman R, Murdock DK. Comparison of effectiveness and safety of ranolazine versus amiodarone for preventing atrial fibrillation after coronary artery bypass grafting. Am J Cardiol 2011; 108: 673-6. [PubMed: 21726841]

  (Among 393 patients undergoing bypass grafting who were treated with either amiodarone or ranolazine for 14 days, there was a higher rate of atrial fibrillation with ranolazine [26.5% vs 17.5%]; no mention of changes in ALT levels during therapy).
• Sendón JL, Lee S, Cheng ML, Ben-Yehuda O; CARISA study investigators. Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally-tolerated background therapy: analysis from the Combination Assessment of Ranolazine In Stable Angina (CARISA) randomized trial. Eur J Prev Cardiol 2012; 19: 952-9. [PubMed: 22689417]

  (In a post hoc analysis of a trial of 2 doses of ranolazine vs placebo in patients with chronic angina [Chaitman 2004] focusing upon patients receiving the maximally tolerated dose, ranolazine decreased angina symptoms and adverse events were similar to what has been previously published).
• Sancho-del-Val L, Barrio-Andrés J, Herranz-Bachiller MT, Alcaide-Suárez N. Hepatotoxicity and insomnia secondary to ranolazine. Rev Esp Enferm Dig 2013; 105: 304-5. [PubMed: 23971665]

  (63 year old woman with angina developed fatigue and serum enzyme elevations without jaundice 3 months after starting ranolazine, symptoms and liver tests improving once the drug was stopped: Case 1).
• Aldakkak M, Stowe DF, Camara AK. Safety and efficacy of ranolazine for the treatment of chronic angina pectoris. Clin Med Insights Ther 2013; 2013: 1-14. [PMC free article: PMC3932785] [PubMed: 24574825]

  (Review of safety and efficacy of ranolazine as therapy of angina discusses common side effects of dizziness, nausea, constipation, headache and fatigue and minor laboratory changes such as increases in creatinine and eosinophils and decreases in hematocrit and HbA1c levels; no mention of changes in ALT or hepatotoxicity).
• De Ferrari GM, Maier LS, Mont L, Schwartz PJ, Simonis G, Leschke M, Gronda E, et al.; RAFFAELLO Investigators. Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO study. Heart Rhythm 2015; 12: 872-8. [PubMed: 25602175]

  (Among 238 patients undergoing cardioversion for atrial fibrillation treated with ranolazine [375, 500 or 750 mg twice daily] or placebo, the 2 higher doses reduced recurrence of fibrillation; side effects included fatigue [16-17% vs 9% with placebo] and there were no liver related serious adverse events and “no significant changes in safety laboratory tests”).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury from the US enrolled in a prospective database between 2004 and 2012, none were attributed to ranolazine).
• Alexopoulos D, Kochiadakis G, Afthonidis D, Barbetseas J, Kelembekoglou P, Limberi S, Spanos A, et al. Ranolazine reduces angina frequency and severity and improves quality of life: Observational study in patients with chronic angina under ranolazine treatment in Greece (OSCAR-GR). Int J Cardiol 2016; 205: 111-6. [PubMed: 26730841]

  (Among 189 patients with chronic angina treated with ranolazine for 6 months, angina symptoms decreased and quality of life indices improved, while side effects were usually mild and “no adverse events involving routine laboratory values were reported”).
• Olivotto I, Camici PG, Merlini PA, Rapezzi C, Patten M, Climent V, Sinagra G, et al. Efficacy of ranolazine in patients with symptomatic hypertrophic cardiomyopathy: the RESTYLE-HCM randomized, double-blind, placebo-controlled study. Circ Heart Fail 2018; 11: e004124. [PubMed: 29321131]

  (Among 80 adults with hypertrophic cardiomyopathy treated with ranolazine or placebo for 5 months, ranolazine had no overall effect on exerice performance or quality of life, but was well tolerated with similar rates of adverse events as with placebo and ALT elevations in only one treated subject).