DRUG FORECAST. 488 P&T September 2007 Vol. 32 No. 9

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1 Ranolazine (Ranexa): A First-in-Class Therapy for Stable Angina Marilena S. Antonopoulos, PharmD, Julie N. Lee, BSMT, PharmD, and Albert V. Chang, BS, PharmD INTRODUCTION Angina pectoris (chest pain) is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back, or arm. It occurs when the myocardial demand for oxygen (MVO 2 ) exceeds the oxygen supply, leading to myocardial ische mia. Typically, angina is the result of coronary artery disease (CAD), also known as ischemic heart disease (IHD) and coronary heart disease (CHD). 1 CHD remains the single leading cause of death in the U.S., 2 afflicting 13.2 million Americans and accounting for 20% of all deaths. 2,3 Approximately 6.5 million people in the U.S. experience angina, with 400,000 new cases of stable angina emerging annually in the U.S. 2,3 Stable angina typically occurs with physical exertion or emotional stress and is relieved by rest, nitroglycerin, or both. It is often predictable and reproducible, typically lasting for several minutes. Unstable angina, which falls under the umbrella term of acute coronary syndrome (ACS), occurs at rest, is characterized by a longer duration, and is often more painful than stable angina. 1 Most cases of CHD are caused by atherosclerosis of the epicardial vessels. 1 In addition to stable and unstable angina, other manifestations of atherosclerosis Dr. Antonopoulos is Assistant Professor of Pharmacy Practice at Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, in Brooklyn, New York, and a Clinical Pharmacy Specialist in Inter nal Medicine at the New York Harbor Healthcare System, Department of Veterans Affairs in New York, New York. At the time of this writing, Dr. Lee and and Dr. Chang were students at Long Island University. Dr. Lee is a pharmacy intern in Brooklyn. Dr. Chang is a licensed pharmacist in New York. Drug Forecast is a regular department coordinated by Alan Caspi, PhD, PharmD, MBA, President of Caspi & Associates in New York. Disclosure: The authors have no relationships to disclose relevant to this article. include heart failure, myocardial infarction (MI), stroke, peripheral arterial disease, and arrhythmias. 1 Several risk factors can predispose patients to CHD and lead to its progression: smoking, diabetes, hypertension, hyperlipidemia, obesity, and a sedentary lifestyle. 4 Appropriate identification and treatment of CHD risk factors play a crucial role in the management of CHD (Figure 1). Treatment goals for patients with stable angina are to reduce the risk of mortality and morbid events, such as MI, arrhy thmias, and heart failure. Treatment is also aimed at reducing or elim - inating angina symptoms, thereby improving patients quality of life and increasing their exercise capability. 4 Until recently, three major classes of anti-ischemic drugs were available for the medical management of chronic stable angina: nitrates, beta blockers, and calcium-channel blockers (CCBs). Some patients may require a procedure in addi - tion to medical therapy, such as percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Episodes of chronic stable angina are typically precipitated by an increase in MVO 2 in the setting of a fixed decrease in the oxygen supply. 1 This decrease is a result of atherosclerotic plaque formation and progression of CAD. The major determinants of MVO 2 are heart rate, intramyoc ardial wall tension, and myo - cardial contractility. 1 Antianginal drugs exhibit their effects by reducing the differen t components of MVO 2. Current practice guidelines recommend the use of a beta blocker as a first-line anti-ischemic therapy in the absence of contraindications (Table 1). CCBs or long-acting nitrates may be used when a beta blocker is contraindicated, or they may be used in combination with a beta blocker if suboptimal results are achieved with initial betablocker treatment. 4 Despite the use of traditional anti - anginal agents and revascularization procedures, anginal episodes still occur. These episodes, in turn, can decrease patients quality of life by limiting their functional independence and their ability to perform daily physical activities. Many patients, particularly in the elderly age group, have relative intolerance to full doses of these agents (see Table 1). On January 27, 2006, the Food and Drug Administration (FDA) approved extended-release ranolazine (Ranexa, CV Therapeutics) as a new molecular entity in the U.S. for patients with chronic angina who continue to be symptomatic after beta-blocker, CCB, or nitrate therapy. 5 It is the first drug in more than 10 years that has been approve d to treat chronic angina. 5 PHARMACOLOGY 6 An active piperazine derivative, rano l - azine is a racemic mixture that is chemically designated as 1-piperazine acet - amide, N-(2,6-dimethylphenyl)-4-[2- methoxyphenoxy)propyl]. Its empirical formula is C 24 H 33 N 3 O 4, and the molecular weight is g/mole. Figure 2 illustrates the agent s chemical structure. A white to off-white solid, the light orang e, film-coated, extended-release A Aspirin and antianginal therapy B Beta blocker and blood pressure C Cigarette smoking and cholesterol D Diet and diabetes E Education and exercise Figure 1 Treatment mnemonic for managing patients with chronic, stable angina. (From Gibbons RJ, et al. ACC/AHA 2002 guideline update. 4 ) 488 P&T September 2007 Vol. 32 No. 9

2 tablet for oral administration contains 500 mg of ranolazine. The tablet is soluble in dichloromethane and methanol and is only slightly soluble in water. In - active tablet ingredients include carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (type C), microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium hydroxide, titanium dioxide, and FD&C Yellow #6 Lake. MECHANISM OF ACTION Ranolazine s precise mechanism of action is unknown. The drug exhibits anti anginal and anti-ischemic effects that are not dependent upon the heart rate or on blood pressure reductions. In ad - ditio n, ranolazine does not appear to increase the rate-pressure product at maximal exercise (a measure of MVO 2, which is the product of heart rate and systolic blood pressure). 1,6 Ranolazine was initially believed to exert its clinical effects by inhibiting fatty acid oxidation, 5 which leads to a shift in myocardial energy production from fatty acid oxidation to glucose oxidation. This, in turn, would produce a higher amount of adenosine triphosphate per oxygen mol - ecule consumed; 7 however, these pharmacological effects were observed at concentrations that exceeded the therapeutic concentrations observed in human clinical trials (more than 10 μmol/l). 8 More recent evidence suggests that ranolazine may exhibit its antianginal effec ts via an electrophysiological mechanism. It is believed that ranolazine selectively inhibits the late sodium current, 8 which is augmented in certain pathological conditions (Table 2). The increase in intracellular sodium ultimately results in an increase in intracellular calcium, which in turn leads to myocardial dysfunction and increased MVO 2 resulting from increased stiffness of the left ventricular diastolic wall. This elevated wall H N O N Table 1 Adverse Effects of Anti-ischemic Therapy Drug Class Beta blockers Calcium-channel blockers Long-acting nitrates tension leads to extravascular compression of coronary vessels and a sub - sequent decreased myocardial oxygen supply. 8,9 Because ranolazine does not prevent ischemia through the same mechanism as the other antianginal agents, it looks promising as an effective complement to current anginal therapy. PHARMACOKINETICS 6,8 Ranolazine undergoes rapid and extensiv e metabolism in the liver and Figure 2 Chemical structure of ranolazine (Ranexa). (From CV Therapeutics, Inc. 6 ) N Adverse Effects Bradycardia Hypotension Heart failure Atrioventricular block Bronchospasm Altered glucose metabolism Impotence Fatigue Depression Lipid abnormalities Abrupt withdrawal symptoms Bradycardia Hypotension Atrioventricular block Headache Dizziness Reflex tachycardia Peripheral edema Constipation Postural hypotension Dizziness Headache Flushing Reflex tachycardia Data from DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 6th ed. New York, NY: McGraw-Hill; 2005: ; 1 and Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina. 4 OH O OMe intes tine; less than 5% of the drug is excret ed unchanged in the urine and feces. It is metab olized mainly by the cyto chrome P450 (CYP) 3A4 mediated pathway and, to a lesser extent, by the CYP 2D6 pathway to multiple metabolites. The four most abundant ones are three phase 1 metabolites (CVT-2512, CVT-2514, CVT-2738) and one phase 2 metabolite. 8 These metabolites have plasma area-under-the-curve (AUC) concentration ranges from approximately 5% to 33% of those of ranol azine. The elimination half-life period is six to 22 hours. No clinically significant effects on the pharmacokinetic parameters of ran - olazine have been identified on the basis of patient age or sex. According to data from a pharmacokinetic study in patients with varying degrees of renal insufficiency, ranolazine plasma levels appear to increase by about 50% in this patient population. In patients with hepatic impairm ent, plasma concentrations of Vol. 32 No. 9 September 2007 P&T 489

3 Table 2 Cardiovascular Conditions Associated with Amplified Late Sodium Current (I NA ) Activity Heart failure Acute and chronic myocardial ischemia Ventricular and supraventricular arrhythmias Cardiac sodium channel gene mutations Data from Chaitman BR. Circulation 2006;113: ran olazine increased by 1.3-fold and by 1.6-fold in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) liver impairment, respectively. The pharmacokinetic properties of ran olazine in patients on dialysis or in patients younger than 18 years of age have not been investigated. 6 Evaluations of patients with heart failure (New York Heart Association [NYHA] Classes I IV) and of patients with diabetes mellitus show no effects on ran - olazine pharmacokinetics. 6 PHARMACODYNAMIC EFFECTS 6 Ranolazine exhibits minimal changes in mean heart rate (less than 2 beats/ minute) and systolic blood pressure (less than 3 mm Hg), as observed in controlled studies of patients with chronic angina who were treated with this medication. 10,11 Results were similar for patients with heart failure NYHA Class I or II, diabetes, or reactive airways disease and who were elderly. Some subjects (N = 6) with severe renal impairment who were taking ranolazine 500 mg twice daily by mouth experienced mean diastolic blood pressure increases of approxima tely 10 to 15 mm Hg. 6 Ranolazine causes dose-related and plasma-related increases in the corrected QT (QTc) interval, reductions in T-wave amplitude, and fewer notched T waves. These effects appear to be a result of the drug, not its metabolites. The pharmacokinetic relationship between plasma ran - olazine concentrations and a prolonged QTc interval is linear, with a slope of approxim ately 2.6 milliseconds (msec) per 1,000 ng/ml of ranolazine. The slope is steeper in patients with mild, moderate, or severe hepatic impairment, with three-fold increases in prolonged QTc effects. 6 The time of maximum concentration (T max ) after continuous dosing of ran - olazine 1,000 mg twice daily results in a mean QTc change of approximately 6 msec. The top 5% of patients with the highest plasma concentrations experienced a QTc prolongation of at least 15 msec. 6 CLINICAL EFFICACY The CARISA Trial 10 In the Combination Assessment of Ranolazine In Stable Angina (CARISA) study, a multicenter, randomized, double-blind, three-group parallel trial, 823 patients with symptomatic chronic angina received placebo twice daily or sustained-release ranolazine 750 mg or 1,000 mg twice daily for 12 weeks. To be eligible for enrollment, study participants had to have: CAD, as confirmed by angiography. a documented prior MI. a diagnostic stress myocardial imaging study. a history of exertional angina for three months or more. Exclusion criteria were as follows: a resting ST-segment depression of 1 mm or more in any electro cardiographic (ECG) lead left bundle branch block digoxin therapy NYHA Class III or IV heart failure an ACS or coronary revascularization procedure two months prior to enrollment medications that could prolong the QT interval a baseline QTc interval above 500 msec Enrolled patients were symptomatic with chronic angina monotherapy and were allowed to continue their treatment of fixed doses of atenolol 50 mg/day (Tenormin, AstraZeneca), amlodipine besylate 5 mg/day (Norvasc, Pfizer), or extended-release diltiazem 180 mg/day (Cardizem, Biovail). The patients were stratified according to the antianginal therapy that they were taking at the time of enrollment (43% were taking atenolol, 31% were taking amlodipine, and 26% were taking diltiazem). Patients were also permitted to use sublingual nitroglycerin. Exercise treadmill tests were performed. Peak drug levels (four hours after drug administration) were assessed at weeks 2 and 12. Trough drug levels (12 hours after drug administration) were assessed at weeks 2, 6, and 12 (Table 3). The primary objective of CARISA was to compare the duration of treadmill exer cise in patients taking ranolazine or placebo at trough ranolazine levels. Secondary objectives analyzed (1) treadmill exercise duration at peak ranolazine levels, (2) times to onset of angina and to 1-mm, ST-segment depression in treadmill exercise test at peak and trough concentrations, and (3) the use of sublingual nitroglycerin, as documented in patients diaries. Vital signs and adverse drug events (ADEs) were also assessed. Most enrolled participants (75% 80%) were male, with an average age of 64 years. Peak serum ranolazine levels helped in prolonging the duration of exercise time by 34 seconds with 750 mg twice daily (P = 0.001) and by 26.1 seconds with 1,000 mg twice daily (P = 0.02), compared with placebo. At peak ran olazine levels, drug therapy extended the onset of exercise-induced angina by 38 seconds in both groups, compared with placebo (P = and 0.003, respectively). Trough ranolazine serum levels indicated an improved duration of exercise by 23.7 seconds with ranolazine 750 mg twice daily (P = 0.03) and by 24 seconds with a dose of 1,000 mg twice daily (P = 0.03), compared with placebo. The onset of exercise-induced angina was also prolonged by 29.7 seconds with ranolazine 750 mg twice daily (P = 0.01) and by 26 seconds with a dose of 1,000 mg twice daily (P = 0.002), compared with placebo. At baseline, patients in all treatment groups had an average of 4.5 anginal attacks per week. After treatment, the rates per week were reduced to 3.3 attacks with placebo, 2.5 attacks with ran - olazine 750 mg twice daily (P = 0.006), 490 P&T September 2007 Vol. 32 No. 9

4 and 2.1 attacks with ranolazine 1,000 mg twice daily (P < 0.001). Nitroglycerin use brought about similar reduced rates of angina attacks. With standard doses of ranolazine, there was no appreciable drop in blood pressure (2.8 mm Hg, P = 0.02) or heart rate (2.8 beats/minute, P = 0.02) at rest or at the end of exercise. Ranolazine did not demonstrate clinically meaningful changes in standing or end-of-exercise blood pressures or in heart rates (Table 4), although some changes did demonstrate statistical significance. Tolerance to ranolazine did not develop during the 12 weeks of therapy. During the 12-week trial, mortality rates were 1.1% (3/269) in the placebo patients, 0.7% (2/279) in the ranolazine 750-mg group, and 0.4% (1/275) in the ran olazine 1,000-mg group. The ERICA Trial 11 The Efficacy of Ranolazine In Chronic Angina (ERICA) study was a multicenter, randomized, placebo-controlled, parallelgroup trial. The investigators sought to determine whether ranolazine plus amlodipin e, at the maximum recommended daily dose of 10 mg, would improve angina in stable patients con - tinuing to experience persistent symptoms despite taking amlodipine 10 mg daily. To be enrolled, patients had to meet these criteria: They had to be 18 years of age or older. They had to have a documented history of CAD. They had to have chronic stable angina for three months or more. They had to have three or more episodes of angina per week despite treatment with amlodipine 10 mg/ day during a two-week prequalification period. Exclusion criteria consisted of: NYHA Class IV heart failure. a history of MI or unstable angina within the previous two months, torsades de pointes (atypical tachy - cardia), active acute myocarditis, pericarditis, hypertrophic cardio - myopathy, or uncontrolled hypertension. a baseline QTc interval above 500 msec. concomitant use of CYP 3A4 inhib - itors or medications that prolong the QTc interval. clinically significant hepatic disease. Table 3 Treadmill Exercise Data from the CARISA Trial At Peak Ranolazine Serum Levels Ranolazine Ranolazine Placebo 750 mg 1,000 mg (n = 256) (n = 270) (n = 255) Mean exercise duration at baseline (seconds) Change from baseline* (seconds) P value vs. placebo Mean time to onset of angina at baseline (seconds) Change from baseline (seconds) P value vs. placebo Mean time to ECG ischemia at baseline (seconds) Change from baseline (seconds) P value vs. placebo < At Trough Ranolazine Serum Levels Ranolazine Ranolazine Placebo 750 mg 1,000 mg (n = 258) (n = 272) (n = 261) Mean exercise duration at baseline (seconds) Change from baseline* (seconds) P value vs. placebo Mean time to onset of angina at baseline (seconds) Change from baseline (seconds) P value vs. placebo Mean time to ECG ischemia at baseline (seconds) Change from baseline (seconds) P value vs. placebo CARISA = Combination Assessment of Ranolazine in Stable Angina; ECG = electrocardiogram. * Changes from baseline are to the last observation carried forward. Data from Chaitman BR, Pepine CJ, Parker JO, et al. JAMA 2004;291: Vol. 32 No. 9 September 2007 P&T 491

5 a creatinine clearance below 30 ml/minute. a chronic illness that precluded compliance with medication. current use of digitalis, perhexilene maleate (Pexid), trimetazidine (Vas - tarel), beta blockers, or CCBs (other than amlodipine). A total of 565 patients received either ranolazine extended-release 500-mg tablets (n = 281) twice daily or placebo (n = 284) during the first week, then 1,000 mg (ranolazine or placebo) twice daily for the full-dose treatment phase (at six weeks). All subjects received amlodipine 10-mg tablets once daily. Patients used sublingual nitroglycerin tablets to treat angina episodes on an as-needed basis. Patients were permitted to use longacting nitrates in conjunction with amlodipine if they were taking a stable dose of the nitrates two or more weeks before entry into the study. Long-acting nitrates were used by 43% of the placebo patients and by 46% of the ranolazine patients. The primary endpoint measured the patient-reported weekly average frequency of anginal episodes during the full-dose treatment phase. Secondary endpoints were the average weekly nitro - glycerin consumption rate and the change from baseline of the five dimensions of the Seattle Angina Questionnaire (SAQ): frequency of angina, physical limitation, anginal stability, disease perceptio n, and treatment satisfaction. These endpoints were given scores ranging from 0 to 100. At the end of the six-week treatment phase, the ranolazine group experienced significantly fewer weekly anginal epi - sodes (2.88) than the placebo group (3.31) (P = 0.028) as well as a significantly lower weekly nitroglycerin consumption rate (2.03 tablets) than the placebo group (2.68 tablets) (P = 0.014). SAQ scores evaluating anginal frequency were significantly improved in the ranolazine patients, compared with the placebo group. The mean change from baseline scores was 22.5 points versus 18.5 points (P = 0.008). No significant differences were observed in the other dimensions measured. As with the CARISA trial, most study participants were male (approximately 73%); the average age of the participants was 62 years. ADVERSE DRUG REACTIONS 6,10,11 The most common adverse drug re - actions reported by patients receiving ranolazine in clinical trials were consti - pation, dizziness, nausea, peripheral edema, and asthenia. The incidence of ADEs occurred in a dose-dependent manner, with the higher 1,000-mg dose of ranolazine resulting in more adverse reactions. In the CARISA trial, no signs, symptoms, or electrocardiographic evidence of ventricular tachyarrhythmias was noted. Small, dose-related increases in QTc were observed with the study drug, compared with placebo. At week 12, the mean QTc interval was elongated by 6.1 Table 4 Hemodynamic Effects of Ranolazine from the CARISA Trial Ranolazine Ranolazine 750 mg 1,000 mg Mean change in systolic blood pressure Not reported Standing Peak drug levels 2.8 mm Hg (P = 0.02) Trough drug levels 2.8 mm Hg (P = 0.02) End-exercise Peak levels 0 Trough drug levels 3.3 mm Hg (P = 0.04) Mean change in end-exercise heart rate Peak 2.3 bpm (P = 0.05) 2 bpm (P = 0.09) Trough 3.1 bpm (P = 0.01) 2.8 bpm (P = 0.02) bpm = beats/minute; CARISA = Combination Assessment of Ranolazine in Stable Angina. Data from Chaitman BR, Pepine CJ, Parker JO, et al. JAMA 2004;291: msec with ranolazine 750 mg and by 9.2 msec with ranolazine 1,000 mg, compared with placebo (P < 0.001). Torsades de pointes did not develop in any of the ranolazine-treated patients. In the ERICA trial, ADEs were documented in 35.5% of patients who received placebo and in 39.9% of those who received ranolazine. Most ADEs were mild to moderate in severity, with constipation the most common complaint (8.9% with ranolazine; 1.8% with placebo). Other ADEs included peripheral edema (5.7% for ranolazine; 2.8% for placebo); dizziness (3.9%, ranolazine; 2.5%, placebo), nausea (2.8%, ranolazine; 0.7%, placebo), and headache (2.8%, ran - olazine; 2.5%, placebo). No significant changes were reported from baseline values in supine blood pressure, standing systolic blood pressure, or heart rate in either treatment group. DOSAGE AND ADMINISTRATION 6 The recommended initial dose of ran - olazine is 500 mg (one tablet) twice daily. If needed, the dose can be subsequently increased to 1,000 mg twice daily, depending on clinical symptoms. Current guidelines recommend not exceeding 1,000 mg twice daily. Because ranolazine prolongs the QTc interval, this drug should be reserved for patients who have not achieved an adequate response with other antianginal medications. It should be used as add-on therapy with amlodipine, beta blockers, or nitrates. The concomitant use of medicatio ns that cause QTc prolongation or increased ranolazine plasma concentrations should be avoided (see Drug Interactions). Ranolazine tablets should be swallowed whole and may be taken without regard to meals. Because this agent is available as an extended-release formulation only, the tablets should not be crushed, broken, or chewed. DRUG INTERACTIONS 6 Ranolazine should not be taken with potent or moderately potent CYP 3A4 inhibitors such as ketoconazole (Nizoral, Janssen) or with other antifungal agents, dil - tiazem, verapamil (Calan, Pfizer), protease inhibitors, macrolide 492 P&T September 2007 Vol. 32 No. 9

6 antibiotics, or grapefruit juice. Coadmin - istration of these agents has resulted in two-fold to three-fold increases in ranolazine plasma concentrations in vivo. Studies evaluating the use of ranolazine with CYP 3A inducers have not been conducted. In vitro studies indicate that ranolazine is a P-glycoprotein (P-gp) substrate. Caution should be used when ranolazine is coadministered with P-gp inhibitors such as ritonavir (Norvir, Abbott), cyclo - sporine, and verapamil. As both a CYP 3A4 inhibitor and a P-gp inhibi tor, verapamil is contraindicated with ranolazine. Ranolazine is a P-gp inhibitor and raises serum digoxin levels by 1.5-fold to two-fold. Ranolazine is also a weak inhib - it or of CYP 3A4 and 2D6 isoenzymes. The dose may need to be reduced with medications that are metabolized through these pathways (such as simvastatin [Zocor, Merck], tricyclic anti - depressants, and some antipsychotic agents) when ranolazine is administered concomitantly. No adjustments are necessary when ranolazine is used with CYP 2D6 inhibitors because of the limited role that CYP 2D6 plays in the metabolism of ranolazine. To date, no drug drug interactions with warfarin (Coumadin, Bristol-Myers Squibb) have been reported. Because ranolazine produces dosedependen t increases in the QTc interval, it should not be used with QTc-prolonging agents (i.e., some antiarrhythmic and antipsychotic agents). CONTRAINDICATIONS 6 Ranolazine is contraindicated in those patients with pre-existing QT prolongation or in those who are taking QTprolongin g medications, in patients with hepatic impairment (Child-Pugh Classes A, B, and C), and in patients receiving potent and moderately potent CYP 3A4 inhibitors (see Drug Interactions). COST Ranolazine (Ranexa) is available as 500-mg extended-release tablets. As of July 2007, the average wholesale price of a 60-tablet bottle was $ CONCLUSION Ranolazine is a pioneer drug in its class. It possesses additional antianginal benefits for patients currently taking anti - anginal therapy who continue to experience anginal symptoms. Its proposed unique mechanism of action adds complementary benefits to conventional anti - anginal therapy. If used correctly, this agent has the potential to improve symptoms of patients with chronic angina who are already using antianginal therapy. REFERENCES 1. Talbert RL. Ischemic heart disease. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approac h, 6th ed. New York: McGraw- Hill; 2005: American Heart Association. Heart Attack and Angina Statistics Available at: Accessed March 21, Thom T, Haase N, Rosamon W, et al. Heart disease and stroke statistics: 2006 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulati on 2006;113: Available at: Accessed March 15, Gibbons RJ, Abrams J, Chatterjee K, et al. American College of Cardiology/American Heart Association 2002 guideline update for the management of patients with chronic stable angina. Available at: science/clinical/statements.htm. Accessed March 20, FDA news release. FDA approves new treatment for chest pain. Available at: NEW01306.html. Accessed March 15, Ranexa (ranolazine), package insert. Palo Alto, CA: CV Therapeutics, Inc.; February Anderson JR, Nawarskas JJ. Ranolazine: A metabolic modulator for the treatment of chronic stable angina. Cardiol Rev 2005;13: Chaitman BR. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation 2006;113: Belardinelli L, Shryock JC, Fraser H. The mechanism of ranolazine action to reduce ischemia-induced diastolic dysfunction. Eur Heart J Suppl 2006;8:A10 A Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlo dipine, or diltiazem on exercise tolerance and angina frequency in patients with sever e chronic angina: A randomized controlled trial. JAMA 2004;291: Stone PH, Gratsiansky NA, Blokhim A, et al. Antianginal efficacy of ranolazine when added to treatment with amlo d - ipine. J Am Coll Cardiol 2006;48: McKesson Drug Database. Accessed March 30, Vol. 32 No. 9 September 2007 P&T 493