New Drug Reviews
Ranolazine (Ranexa) for Chronic Angina
Am Fam Physician. 2007 Feb 15;75(4):544-546.
Ranolazine (Ranexa) represents a new class of drugs known as metabolic modulators. It is labeled for use in combination with amlodipine (Norvasc), beta blockers, or nitrates in patients with chronic angina who have not had adequate antianginal responses. Although the exact mechanism of action is unknown, ranolazine seems to increase the efficiency of energy production in the heart, maintaining cardiac function without reducing heart rate or blood pressure.1
|Name||Starting dosage||Dose form||Approximate monthly cost*|
500 mg orally twice daily; if needed, increase to 1,000 mg twice daily
500-mg extended-release tablet
*— Average wholesale cost, based on Red Book, Montvale, N.J.: Medical Economics Data, 2006.
Ranolazine prolongs the QTc interval in a dose-related manner, particularly in persons with mild, moderate, or severe hepatic dysfunction. It is contraindicated in patients with preexisting QT prolongation, including congenital long QT syndrome, uncorrected hypokalemia, and hepatic impairment. The manufacturer does not state when the drug should be discontinued if QT interval prolongation occurs, only that modest QT prolongation (four to six milliseconds) is associated with torsades de pointes arrhythmia. Ranolazine also has been reported to increase blood pressure by approximately 15 mm Hg in patients with severe renal impairment.1,2
Ranolazine should not be used in patients taking any medication that also prolongs the QT interval or inhibits the CYP3A enzyme system; this includes numerous medications. Potential drug-drug and drug-food interactions should be evaluated before starting ranolazine or when adding any therapy. Ranolazine is a U.S. Food and Drug Administration pregnancy category C drug. It is not known whether it is distributed in breast milk.1,2
In controlled studies of patients with angina, approximately 6 percent of those receiving ranolazine discontinued treatment because of side effects compared with 3 percent of those receiving placebo.2 Dizziness, headache, and constipation were infrequently reported. Small, reversible elevations in serum creatinine and blood urea nitrogen levels have been reported, but no evidence of renal toxicity was observed.1–4
Ranolazine primarily has been studied in patients who continue to be symptomatic despite pharmacotherapy with other anti-anginal medications, such as beta blockers or calcium antagonists. Patients with persistent angina who were given ranolazine in addition to another treatment experienced fewer episodes of angina attacks per week compared with patients given placebo (3.3 versus 4.3, respectively) and required fewer nitroglycerin doses per week (2.7 versus 3.6, respectively).2,3 When added to a regimen of maximal dose amlodipine, ranolazine significantly reduced the frequency of angina episodes per week compared with placebo (2.9 versus 3.3, respectively) and weekly nitroglycerine uses (2.0 versus 2.7, respectively).4
Ranolazine therapy increased exercise tolerance, but the average increase was only 30 seconds longer than that seen with placebo (2.0 and 1.5 minutes, respectively).2,5 Increases in exercise duration and decreases in exercise-induced ischemia and angina episodes were similar to those seen with atenolol (Tenormin) but without decreasing blood pressure or heart rate.6 To date, no studies have been conducted to measure the effects of ranolazine on mortality or the progression of coronary heart disease.
The addition of ranolazine to beta blockers, calcium antagonists, or nitrates would cost approximately $206 for a one-month supply (60 tablets, 500 mg each).
The recommended starting dosage of ranolazine is one tablet (500 mg) twice daily. It can be increased to two tablets twice daily as needed based on clinical symptoms. Ranolazine can be taken with or without meals and should be swallowed whole and not crushed, broken, or chewed. Grapefruit juice or products should be avoided. If a dose is missed, it should be taken at the next scheduled time; no doses should be doubled. Baseline and follow-up electrocardiography should be performed to evaluate the QTc interval, and blood pressure should be monitored regularly in patients with severe renal failure.1,2
Ranolazine will provide a small benefit in symptom control in patients with chronic angina and persistent symptoms despite medical therapy. It generally should be used in combination with amlodipine, beta blockers, or long-acting nitrates. Because ranolazine has the potential to induce arrhythmia, it should be reserved for use in patients who have not achieved adequate responses with other antianginal therapies.
1. Ranolazine. In: Drugdex System (internet database). Greenwood Village, Colo.: Thomson Micromedex. Accessed October 26, 2006, at: http://www.thomsonhc.com (subscription required).
2. Ranexa (ranolazine extended-release tablets) [Product information]. Palo Alto, Calif.: CV Therapeutics Inc., 2006.
3. Chaitman BR, Pepine CJ, Parker JO, Skopal J, Chumakova G, Kuch J, et al., for the 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.
4. Stone PH, Gratsiansky NA, Blokhin A, Huang IZ, Meng L, for the ERICA Investigators. 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.
5. Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al., for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375–82.
6. Rousseau MF, Pouleur H, Cocco G, Wolff AA. Comparative efficacy of ranolazine versus atenolol for chronic angina pectoris. Am J Cardiol. 2005;95:311–6.
STEPS new drug reviews cover Safety, Tolerability, Effectiveness, Price, and Simplicity. Each independent review is provided by authors who have no financial association with the drug manufacturer.
The series coordinator for AFP is Allen F. Shaughnessy, Pharm.D., Tufts University Family Medicine Residency Program, Malden, Mass.
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