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Ranolazine Extended-release Tablets (Ranexa®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
Ranolazine has gained expanded approval from the FDA for the treatment of chronic angina. The drug was initially approved in 2006 for the treatment of chronic angina in patients who have not achieved an adequate response with other anti-angina drugs and in combination with amlodipine, beta-blockers, or nitrates. The new approval was based on ranolazine establishing safety in a large trial in patients with acute coronary syndrome.1,2
Ranolazine is indicated for the treatment of chronic angina.3
The recommended dose is 500 mg twice daily and may increase to 1000 mg twice daily based on clinical symptoms. The tablets should be taken whole and may be taken without regard to meals.3
Ranolazine is available as 500 mg and 1000 mg extended-release tablets.
Ranolazine has a different mechanism of action compared to other anti-angina agents (e.g., calcium channel blockers, beta-blockers, nitrates). It exerts its beneficial effect without significant effects on blood pressure, heart rate, or vascular resistance. Ranolazine does not negatively affect lipids or glycemic control and may even improve glycemic control.4
In clinical trials, women benefited less than men in terms of reduction in angina attacks and improved exercise tolerance.3 Ranolazine is contraindicated in patients with significant hepatic and renal impairment. It should not be used in combination with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) and CYP3A inducers (e.g., rifampin, phenobarbital). The most common adverse events are dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness and nausea were the adverse events most likely to lead to discontinuation of therapy during clinical trials.3 In a long-term safety and tolerability study (n = 746), termination of study participation due to unacceptable adverse events was 7.1% at 1 year and 9.7% at 2 years.5
Ranolazine reduces myocardial ischemia without significant effect on heart rate or blood pressure. It is postulated to work by inhibiting the cardiac late phase of inward sodium current during cardiac repolarization. The drug was originally approved in 2006 based on 2 randomized, placebo-controlled trials in subjects with chronic angina; Combination Assessment of Ranolazine In Stable Angina (CARISA) with 823 subjects for 12 weeks and Efficacy of Ranolazine In Chronic Angina (ERICA) with 565 subjects for 6 weeks.6,7 In CARISA, ranolazine (750-1000 mg twice daily) improved treadmill exercise tolerance by about 30 sec (4 hours after dosing) and 24 sec (12 hours after dosing) compared to placebo. Time to angina was similarly improved, ~28 sec and 38 sec, respectively. The mean numbers of angina attacks per week and nitroglycerin doses per week were roughly reduced by 1 with ranolazine (3.3 to 2.5 and 2.1; and 3.1 to 2.1 and 1.8). These effects were statistically significant. In the ERICA trial, with 1000 mg twice daily, the results were similar in terms of mean reductions of attacks (4.3 vs 3.3) and nitroglycerin use (3.6 vs 2.7). The median reductions were less impressive, 2.4 vs 2.2 and 1.7 vs 1.3, suggesting that patients with more frequent attacks are more likely to benefit. In a large study (n = 6560), ranolazine showed no benefit in patients with non-ST elevation acute coronary syndrome in terms of cardiovascular death, MI, or severe recurrent ischemia.2 However, subjects treated with ranolazine had a significantly greater reduction of recurrent ischemia and a lower incidence of arrhythmias, including ventricular tachycardia.1,2 Less than 1% (0.9% vs 0.3% for placebo) of patients required dose reduction due to prolonged QTc. This study allayed the concerns about the proarrhythmic effect of ranolazine based on its potential to prolong QTc and helped gain a broader indication for chronic angina. In a post-hoc analysis of diabetic and nondiabetic subjects in the CARISA trial, ranolazine 750 mg and 1000 mg reduced HbA1c vs placebo by 0.48 ± 0.18% (P = 0.008) and 0.70 ± 0.18% (P = 0.0002), respectively.4
The prevalence of chronic angina is about 3% and the incidence increases with age. These patients continue to have symptoms and evidence of ischemia despite pharmacotherapy.8 Ranolazine provides another option for these patients and possibly adding benefit for those with diabetes or high risk of developing diabetes.
1. Scirica BM, 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. Circulation 2007;116:1647-1652.
2. Morrow DA, 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;297:1775-1783.
3. Ranexa Product Information. Palo Alto, CA: CV Therapeutics, Inc.; November 2008.
4. Timmis AD, et al. Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006;27:42-48.
5. Nash DT, Nash SD. Ranolazine for chronic stable angina. Lancet 2008;372:1335-1341.
6. Chaitman BR, 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;291:309-316.
7. Stone PH, 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;48:566-575.
8. Koren MJ, et al. 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;49:1027-1034.