英文药名：RANEXA(ranolazine extended-release tablets) 中文药名：雷诺嗪缓释片 生产厂家：Gilead Sciences, Inc 药品介绍 Ranolazine 2HCl是一种钙离子通过 sodium/calcium channal摄取的抑制剂抗心绞痛药物，用于治疗慢性心绞痛。 药品特点 ①有效抗心绞痛： 体外研究表明狗麻醉后，十二指肠内给雷诺嗪或阿替洛尔均明显减弱电心脏起搏（200次/分）期间冠状动脉结扎引起的ST-T段上抬。雷诺嗪的这种作用持续3个小时，不改变任何血液动力学参数；而使用阿替洛尔后却伴有舒张期血压、心率的升高或降低。大鼠灌胃给予雷诺嗪，减弱由肾上腺素引起的ST段上抬。这些结果表明雷诺嗪可有效地抗心绞痛，且不改变任何动力学参数。 ②不影响心率和血压： 14名慢性稳定型心绞痛患者参加的单盲安慰剂对照试验中，病人服用安慰剂两周后，口服雷诺嗪30mg（一日三次），连续2周后改为口服60mg（一日三次），连续两周。结果表明：服用两种剂量后测定静息时心率和收缩压、剧烈运动后心率和收缩压分别与安慰剂对照组相比均无明显改变。 ③全新作用机制： 雷诺嗪为pFOX（部分脂肪酸氧化酶）抑制剂，通过改变心脏代谢方式减少心脏需氧量。心脏代谢是利用氧气氧化脂肪酸或葡萄糖产能。正常生理状态下，心肌细胞主要利用脂肪酸氧化产能，而较少利用葡萄糖。pFOX抑制剂减少脂肪酸氧化，而增加葡萄糖氧化。利用每单位氧气，葡萄糖代谢产能较脂肪酸代谢产能多，那么由利用脂肪酸代谢产能变为利用葡萄糖代谢产能则使心脏利用氧做更多功，从而降低心绞痛发作的可能性。鉴于上述全新的作用机制，口服雷诺嗪后不引起心率减慢和血压下降。还可防止乳酸酸中毒，大大增强了使用安全性。 临床疗效 对104例慢性稳定型心绞痛且有持续症状（ST段至少压低0.1mv，运动测试时有心绞痛发作）的患者进行了随机双盲交叉试验，单剂量给雷诺嗪（10，60，120和240mg），发现在240mg剂量下，显著延长运动持续时间和ST段压低1mm的时间。 对312例慢性稳定型心绞痛患者进行了Ⅱ期临床试验，病人随机分为4组，分别服用雷诺嗪267mg(tid)，400mg(bid)，400mg(tid)和安慰剂，一周后踏车运动时间明显延长，ST段压低1.0mm的时间也显著延长。从而得出结论雷诺嗪为有效抗心绞痛药，且具有较好的安全耐受性。 CV公司对雷诺嗪进行的首次关键性Ⅲ期临床试验表明雷诺嗪治疗组病人的踏车运动持续时间较安慰剂对照组显著增加，证明了雷诺嗪抗心绞痛的有效性。 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use RANEXA safely and effectively. See full prescribing information for RANEXA. RANEXA ® (ranolazine) extended-release tablets, for oral use Initial U.S. Approval: 2006 INDICATIONS AND USAGE RANEXA is an antianginal indicated for the treatment of chronic angina. (1) DOSAGE AND ADMINISTRATION 500 mg twice daily and increase to 1000 mg twice daily, based on clinical symptoms (2.1) DOSAGE FORMS AND STRENGTHS Extended-release tablets: 500 mg, 1000 mg (3) CONTRAINDICATIONS Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4, 7.1) CYP3A inducers (e.g., rifampin, phenobarbital, St. John's wort) (4, 7.1) Liver cirrhosis (4, 8.6) WARNINGS AND PRECAUTIONS QT interval prolongation: Can occur with ranolazine. Little data available on high doses, long exposure, use with QT interval-prolonging drugs, potassium channel variants causing prolonged QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. (5.1) Renal failure: Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL<60 mL/min). If acute renal failure develops, discontinue RANEXA. (5.2) ADVERSE REACTIONS Most common adverse reactions (> 4% and more common than with placebo) are dizziness, headache, constipation, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc., at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit RANEXA to 500 mg twice daily. (7.1) P-gp inhibitors (e.g., cyclosporine): Ranolazine exposure increased. Titrate RANEXA based on clinical response. (7.1) CYP3A substrates: Limit simvastatin to 20 mg when used with RANEXA. Doses of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may need to be reduced with RANEXA. (7.2) OCT2 substrates: Limit the dose of metformin to 1700 mg daily when used with RANEXA 1000 mg twice daily. Doses of other OCT2 substrates may require adjusted doses. (7.2) Drugs transported by P-gp (e.g., digoxin), or drugs metabolized by CYP2D6 (e.g., tricyclic antidepressants) may need reduced doses when used with RANEXA. (7.2) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 1/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE RANEXA® is indicated for the treatment of chronic angina. RANEXA may be used with beta-blockers, nitrates, calcium channel blockers, anti-platelet therapy, lipid-lowering therapy, ACE inhibitors, and angiotensin receptor blockers. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information Initiate RANEXA dosing at 500 mg twice daily and increase to 1000 mg twice daily, as needed, based on clinical symptoms. Take RANEXA with or without meals. Swallow RANEXA tablets whole; do not crush, break, or chew. The maximum recommended daily dose of RANEXA is 1000 mg twice daily. If a dose of RANEXA is missed, take the prescribed dose at the next scheduled time; do not double the next dose. 2.2 Dose Modification Dose adjustments may be needed when RANEXA is taken in combination with certain other drugs [see Drug Interactions (7.1)]. Limit the maximum dose of RANEXA to 500 mg twice daily in patients on moderate CYP3A inhibitors such as diltiazem, verapamil, and erythromycin. Use of RANEXA with strong CYP3A inhibitors is contraindicated [see Contraindications (4), Drug Interactions (7.1)]. Use of P-gp inhibitors, such as cyclosporine, may increase exposure to RANEXA. Titrate RANEXA based on clinical response [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS RANEXA is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths: 500 mg tablets are light orange, with GSI500 on one side 1000 mg tablets are pale yellow, with GSI1000 on one side 4 CONTRAINDICATIONS RANEXA is contraindicated in patients: Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)] Taking inducers of CYP3A [see Drug Interactions (7.1)] With liver cirrhosis [see Use in Specific Populations (8.6)] 5 WARNINGS AND PRECAUTIONS 5.1 QT Interval Prolongation Ranolazine blocks IKr and prolongs the QTc interval in a dose-related manner. Clinical experience in an acute coronary syndrome population did not show an increased risk of proarrhythmia or sudden death [see Clinical Studies (14.2)]. However, there is little experience with high doses (> 1000 mg twice daily) or exposure, other QT-prolonging drugs, potassium channel variants resulting in a long QT interval, in patients with a family history of (or congenital) long QT syndrome, or in patients with known acquired QT interval prolongation. 5.2 Renal Failure Acute renal failure has been observed in some patients with severe renal impairment (creatinine clearance [CrCL] < 30 mL/min) while taking RANEXA. If acute renal failure develops (e.g., marked increase in serum creatinine associated with an increase in blood urea nitrogen [BUN]), discontinue RANEXA and treat appropriately [see Use in Specific Populations (8.7)]. Monitor renal function after initiation and periodically in patients with moderate to severe renal impairment (CrCL < 60 mL/min) for increases in serum creatinine accompanied by an increase in BUN. 6 ADVERSE REACTIONS 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with RANEXA, 1026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks' duration. In addition, upon study completion, 1251 patients received treatment with RANEXA in open-label, long-term studies; 1227 patients were exposed to RANEXA for more than 1 year, 613 patients for more than 2 years, 531 patients for more than 3 years, and 326 patients for more than 4 years. At recommended doses, about 6% of patients discontinued treatment with RANEXA because of an adverse event in controlled studies in angina patients compared to about 3% on placebo. The most common adverse events that led to discontinuation more frequently on RANEXA than placebo were dizziness (1.3% versus 0.1%), nausea (1% versus 0%), asthenia, constipation, and headache (each about 0.5% versus 0%). Doses above 1000 mg twice daily are poorly tolerated. In controlled clinical trials of angina patients, the most frequently reported treatment-emergent adverse reactions (> 4% and more common on RANEXA than on placebo) were dizziness (6.2%), headache (5.5%), constipation (4.5%), and nausea (4.4%). Dizziness may be dose-related. In open-label, long-term treatment studies, a similar adverse reaction profile was observed. The following additional adverse reactions occurred at an incidence of 0.5 to 4.0% in patients treated with RANEXA and were more frequent than the incidence observed in placebo-treated patients: Cardiac Disorders – bradycardia, palpitations Ear and Labyrinth Disorders – tinnitus, vertigo Eye Disorders – blurred vision Gastrointestinal Disorders – abdominal pain, dry mouth, vomiting, dyspepsia General Disorders and Administrative Site Adverse Events – asthenia, peripheral edema Metabolism and Nutrition Disorders – anorexia Nervous System Disorders – syncope (vasovagal) Psychiatric Disorders – confusional state Renal and Urinary Disorders – hematuria Respiratory, Thoracic, and Mediastinal Disorders – dyspnea Skin and Subcutaneous Tissue Disorders – hyperhidrosis Vascular Disorders – hypotension, orthostatic hypotension Other (< 0.5%) but potentially medically important adverse reactions observed more frequently with RANEXA than placebo treatment in all controlled studies included: angioedema, renal failure, eosinophilia, chromaturia, blood urea increased, hypoesthesia, paresthesia, tremor, pulmonary fibrosis, thrombocytopenia, leukopenia, and pancytopenia. A large clinical trial in acute coronary syndrome patients was unsuccessful in demonstrating a benefit for RANEXA, but there was no apparent proarrhythmic effect in these high-risk patients [see Clinical Studies (14.2)]. Laboratory Abnormalities: RANEXA produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function, likely because of inhibition of creatinine's tubular secretion. In general, the elevation has a rapid onset, shows no signs of progression during long-term therapy, is reversible after discontinuation of RANEXA, and is not accompanied by changes in BUN. In healthy volunteers, RANEXA 1000 mg twice daily had no effect upon the glomerular filtration rate. More marked and progressive increases in serum creatinine, associated with increases in BUN or potassium, indicating acute renal failure, have been reported after initiation of RANEXA in patients with severe renal impairment [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)]. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of RANEXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Nervous System Disorders – Tremor, paresthesia, abnormal coordination, and other serious neurologic adverse events have been reported to occur, sometimes concurrently, in patients taking ranolazine. The onset of events was often associated with an increase in ranolazine dose or exposure. Many patients reported symptom resolution following drug discontinuation or dose decrease. Metabolism and Nutrition Disorders – Cases of hypoglycemia have been reported in diabetic patients on antidiabetic medication. Psychiatric Disorders – hallucination Renal and Urinary Disorders – dysuria, urinary retention Skin and Subcutaneous Tissue Disorders – angioedema, pruritus, rash 7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use RANEXA with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4), Clinical Pharmacology (12.3)]. Moderate CYP3A Inhibitors Limit the dose of RANEXA to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. P-gp Inhibitors Concomitant use of RANEXA and P-gp inhibitors, such as cyclosporine, may result in increases in ranolazine concentrations. Titrate RANEXA based on clinical response in patients concomitantly treated with predominant P-gp inhibitors such as cyclosporine [see Dosage and Administration (2.2)]. CYP3A Inducers Do not use RANEXA with CYP3A inducers such as rifampin, rifabutin, rifapentine, phenobarbital, phenytoin, carbamazepine, and St. John's wort [see Contraindications (4), Clinical Pharmacology (12.3)]. 7.2 Effects of Ranolazine on Other Drugs Drugs Metabolized by CYP3A Limit the dose of simvastatin in patients on any dose of RANEXA to 20 mg once daily, when ranolazine is co-administered. Dose adjustment of other sensitive CYP3A substrates (e.g., lovastatin) and CYP3A substrates with a narrow therapeutic range (e.g., cyclosporine, tacrolimus, sirolimus) may be required as RANEXA may increase plasma concentrations of these drugs [see Clinical Pharmacology (12.3)]. Drugs Transported by P-gp Concomitant use of ranolazine and digoxin results in increased exposure to digoxin. The dose of digoxin may have to be adjusted [see Clinical Pharmacology (12.3)]. Drugs Metabolized by CYP2D6 The exposure to CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during co-administration with RANEXA, and lower doses of these drugs may be required. Drugs Transported by OCT2 In subjects with type 2 diabetes mellitus, concomitant use of RANEXA 1000 mg twice daily and metformin results in increased plasma levels of metformin. When RANEXA 1000 mg twice daily is co-administered with metformin, metformin dose should not exceed 1700 mg/day. Monitor blood glucose levels and risks associated with high exposures of metformin. Metformin exposure was not significantly increased when given with RANEXA 500 mg twice daily [see Clinical Pharmacology (12.3)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on RANEXA use in pregnant women to inform any drug-associated risks. Studies in rats and rabbits showed no evidence of fetal harm at exposures 4 times the maximum recommended human dose (MRHD) (see Data). In the U.S. general population, the estimated background risk of major birth defects and of miscarriage of clinically recognized pregnancies is 2–4% and 15–20%, respectively. Data Animal Data Embryofetal toxicity studies were conducted in rats and rabbits orally administered ranolazine during organogenesis. In rats, decreased fetal weight and reduced ossification were observed at doses (corresponding to 4-fold the AUC for the MRHD) that caused maternal weight loss. No adverse fetal effects were observed in either species exposed (AUC) to ranolazine at exposures (AUC) equal to the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of ranolazine in human milk, the effects on the breastfed infant, or the effects on milk production. However, ranolazine is present in rat milk [see Use in Specific Populations (8.1)]. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for RANEXA and any potential adverse effects on the breastfed infant from RANEXA or from the underlying maternal condition. Adult female rats were administered ranolazine orally from gestation day 6 through postnatal day 20. No adverse effects on pup development, behavior, or reproduction parameters were observed at a maternal dosage level of 60 mg/kg/day (equal to the MHRD based on AUC). At maternally toxic doses, male and female pups exhibited increased mortality and decreased body weight, and female pups showed increased motor activity. The pups were potentially exposed to low amounts of ranolazine via the maternal milk. 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Of the chronic angina patients treated with RANEXA in controlled studies, 496 (48%) were ≥ 65 years of age, and 114 (11%) were ≥ 75 years of age. No overall differences in efficacy were observed between older and younger patients. There were no differences in safety for patients ≥ 65 years compared to younger patients, but patients ≥ 75 years of age on RANEXA, compared to placebo, had a higher incidence of adverse events, serious adverse events, and drug discontinuations due to adverse events. In general, dose selection for an elderly patient should usually start at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease, or other drug therapy. 8.6 Use in Patients with Hepatic Impairment RANEXA is contraindicated in patients with liver cirrhosis. In a study of cirrhotic patients, the Cmax of ranolazine was increased 30% in cirrhotic patients with mild (Child-Pugh Class A) hepatic impairment, but increased 80% in cirrhotic patients with moderate (Child-Pugh Class B) hepatic impairment compared to patients without hepatic impairment. This increase was not enough to account for the 3-fold increase in QT prolongation seen in cirrhotic patients with mild to moderate hepatic impairment [see Clinical Pharmacology (12.2)]. 8.7 Use in Patients with Renal Impairment A pharmacokinetic study of RANEXA in subjects with severe renal impairment (CrCL < 30 mL/min) was stopped when 2 of 4 subjects developed acute renal failure after receiving RANEXA 500 mg twice daily for 5 days (lead-in phase) followed by 1000 mg twice a day (1 dose in one subject and 11 doses in the other). Increases in creatinine, BUN, and potassium were observed in 3 subjects during the 500 mg lead-in phase. One subject required hemodialysis, while the other 2 subjects improved upon drug discontinuation [see Warnings and Precautions (5.2)]. Monitor renal function periodically in patients with moderate to severe renal impairment. Discontinue RANEXA if acute renal failure develops. In a separate study, Cmax was increased between 40% and 50% in patients with mild, moderate, or severe renal impairment compared to patients with no renal impairment, suggesting a similar increase in exposure in patients with renal failure independent of the degree of impairment. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis. 8.8 Use in Patients with Heart Failure Heart failure (NYHA Class I to IV) had no significant effect on ranolazine pharmacokinetics. RANEXA had minimal effects on heart rate and blood pressure in patients with angina and heart failure NYHA Class I to IV. No dose adjustment of RANEXA is required in patients with heart failure. 8.9 Use in Patients with Diabetes Mellit A population pharmacokinetic evaluation of data from angina patients and healthy subjects showed no effect of diabetes on ranolazine pharmacokinetics. No dose adjustment is required in patients with diabetes. RANEXA produces small reductions in HbA1c in patients with diabetes, the clinical significance of which is unknown. RANEXA should not be considered a treatment for diabetes. 10 OVERDOSAGE High oral doses of ranolazine produce dose-related increases in dizziness, nausea, and vomiting. High intravenous exposure also produces diplopia, paresthesia, confusion, and syncope. In addition to general supportive measures, continuous ECG monitoring may be warranted in the event of overdose. Severe tremor, unsteady gait/incoordination, dysphasia, and hallucinations have been reported in cases of overdose with RANEXA. Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine. 11 DESCRIPTION RANEXA (ranolazine) is available as a film-coated, non-scored, extended-release tablet for oral administration. Ranolazine is a racemic mixture, chemically described as 1-piperazineacetamide, N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-, (±)-. It has an empirical formula of C24H33N3O4, a molecular weight of 427.54 g/mole, and the following structural formula: Ranolazine is a white to off-white solid. Ranolazine is soluble in dichloromethane and methanol; sparingly soluble in tetrahydrofuran, ethanol, acetonitrile, and acetone; slightly soluble in ethyl acetate, isopropanol, toluene, and ethyl ether; and very slightly soluble in water. RANEXA tablets contain 500 mg or 1000 mg of ranolazine and the following inactive ingredients: carnauba wax, hypromellose, magnesium stearate, methacrylic acid copolymer (Type C), microcrystalline cellulose, polyethylene glycol, sodium hydroxide, and titanium dioxide. Additional inactive ingredients for the 500 mg tablet include polyvinyl alcohol, talc, Iron Oxide Yellow, and Iron Oxide Red; additional inactive ingredients for the 1000 mg tablet include lactose monohydrate, triacetin, and Iron Oxide Yellow. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of ranolazine's antianginal effects has not been determined. Ranolazine has anti-ischemic and antianginal effects that do not depend upon reductions in heart rate or blood pressure. It does not affect the rate-pressure product, a measure of myocardial work, at maximal exercise. Ranolazine at therapeutic levels can inhibit the cardiac late sodium current (INa). However, the relationship of this inhibition to angina symptoms is uncertain. The QT prolongation effect of ranolazine on the surface electrocardiogram is the result of inhibition of IKr, which prolongs the ventricular action potential. 12.2 Pharmacodynamics Hemodynamic Effects Patients with chronic angina treated with RANEXA in controlled clinical studies had minimal changes in mean heart rate (< 2 bpm) and systolic blood pressure (< 3 mm Hg). Similar results were observed in subgroups of patients with CHF NYHA Class I or II, diabetes, or reactive airway disease, and in elderly patients. Electrocardiographic Effects Dose and plasma concentration-related increases in the QTc interval [see Warnings and Precautions (5.1)], reductions in T wave amplitude, and, in some cases, notched T waves, have been observed in patients treated with RANEXA. These effects are believed to be caused by ranolazine and not by its metabolites. The relationship between the change in QTc and ranolazine plasma concentrations is linear, with a slope of about 2.6 msec/1000 ng/mL, through exposures corresponding to doses several-fold higher than the maximum recommended dose of 1000 mg twice daily. The variable blood levels attained after a given dose of ranolazine give a wide range of effects on QTc. At Tmax following repeat dosing at 1000 mg twice daily, the mean change in QTc is about 6 msec, but in the 5% of the population with the highest plasma concentrations, the prolongation of QTc is at least 15 msec. In cirrhotic subjects with mild or moderate hepatic impairment, the relationship between plasma level of ranolazine and QTc is much steeper [see Contraindications (4)]. Age, weight, gender, race, heart rate, congestive heart failure, diabetes, and renal impairment did not alter the slope of the QTc-concentration relationship of ranolazine. No proarrhythmic effects were observed on 7-day Holter recordings in 3162 acute coronary syndrome patients treated with RANEXA. There was a significantly lower incidence of arrhythmias (ventricular tachycardia, bradycardia, supraventricular tachycardia, and new atrial fibrillation) in patients treated with RANEXA (80%) versus placebo (87%), including ventricular tachycardia ≥ 3 beats (52% versus 61%). However, this difference in arrhythmias did not lead to a reduction in mortality, a reduction in arrhythmia hospitalization, or a reduction in arrhythmia symptoms. 12.3 Pharmacokinetics Ranolazine is extensively metabolized in the gut and liver and its absorption is highly variable. For example, at a dose of 1000 mg twice daily, the mean steady-state Cmax was 2600 ng/mL with 95% confidence limits of 400 and 6100 ng/mL. The pharmacokinetics of the (+) R- and (-) S-enantiomers of ranolazine are similar in healthy volunteers. The apparent terminal half-life of ranolazine is 7 hours. Steady state is generally achieved within 3 days of twice-daily dosing with RANEXA. At steady state over the dose range of 500 to 1000 mg twice daily, Cmax and AUC0–τ increase slightly more than proportionally to dose, 2.2- and 2.4-fold, respectively. With twice-daily dosing, the trough:peak ratio of the ranolazine plasma concentration is 0.3 to 0.6. The pharmacokinetics of ranolazine is unaffected by age, gender, or food. Absorption and Distribution After oral administration of RANEXA, peak plasma concentrations of ranolazine are reached between 2 and 5 hours. After oral administration of 14C-ranolazine as a solution, 73% of the dose is systemically available as ranolazine or metabolites. The bioavailability of ranolazine from RANEXA tablets relative to that from a solution of ranolazine is 76%. Because ranolazine is a substrate of P-gp, inhibitors of P-gp may increase the absorption of ranolazine. Food (high-fat breakfast) has no important effect on the Cmax and AUC of ranolazine. Therefore, RANEXA may be taken without regard to meals. Over the concentration range of 0.25 to 10 µg/mL, ranolazine is approximately 62% bound to human plasma proteins. Metabolism and Excretion Ranolazine is metabolized mainly by CYP3A and, to a lesser extent, by CYP2D6. Following a single oral dose of ranolazine solution, approximately 75% of the dose is excreted in urine and 25% in feces. Ranolazine is metabolized rapidly and extensively in the liver and intestine; less than 5% is excreted unchanged in urine and feces. The pharmacologic activity of the metabolites has not been well characterized. After dosing to steady state with 500 mg to 1500 mg twice daily, the four most abundant metabolites in plasma have AUC values ranging from about 5 to 33% that of ranolazine, and display apparent half-lives ranging from 6 to 22 hours. Drug Interactions Effect of Other Drugs on Ranolazine In vitro data indicate that ranolazine is a substrate of CYP3A and, to a lesser degree, of CYP2D6. Ranolazine is also a substrate of P-glycoprotein. Strong CYP3A Inhibitors Plasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 220% when co-administered with ketoconazole 200 mg twice daily [see Contraindications (4)]. Moderate CYP3A Inhibitors Plasma levels of ranolazine with RANEXA 1000 mg twice daily are increased by 50 to 130% by diltiazem 180 to 360 mg, respectively. Plasma levels of ranolazine with RANEXA 750 mg twice daily are increased by 100% by verapamil 120 mg three times daily [see Drug Interactions (7.1)]. Weak CYP3A Inhibitors The weak CYP3A inhibitors simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers. CYP3A Inducers Rifampin 600 mg once daily decreases the plasma concentrations of ranolazine (1000 mg twice daily) by approximately 95% [see Contraindications (4)]. CYP2D6 Inhibitors Paroxetine 20 mg once daily increased ranolazine concentrations by 20% in healthy volunteers receiving RANEXA 1000 mg twice daily. No dose adjustment of RANEXA is required in patients treated with CYP2D6 inhibitors. Digoxin Plasma concentrations of ranolazine are not significantly altered by concomitant digoxin at 0.125 mg once daily. Effect of Ranolazine on Other Drugs In vitro ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A and moderate inhibitors of CYP2D6 and P-gp. In vitro ranolazine is an inhibitor of OCT2. CYP3A Substrates The plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are increased by 100% in healthy volunteers receiving 80 mg once daily and RANEXA 1000 mg twice daily [see Drug Interactions (7.2)]. Mean exposure to atorvastatin (80 mg daily) is increased by 40% following co-administration with RANEXA (1000 mg twice daily) in healthy volunteers. However, in one subject the exposure to atorvastatin and metabolites was increased by ~400% in the presence of RANEXA. Diltiazem The pharmacokinetics of diltiazem is not affected by ranolazine in healthy volunteers receiving diltiazem 60 mg three times daily and RANEXA 1000 mg twice daily. P-gp Substrates Ranolazine increases digoxin concentrations by 50% in healthy volunteers receiving RANEXA 1000 mg twice daily and digoxin 0.125 mg once daily [see Drug Interactions (7.2)]. CYP2D6 Substrates RANEXA 750 mg twice daily increases the plasma concentrations of a single dose of immediate release metoprolol (100 mg), a CYP2D6 substrate, by 80% in extensive CYP2D6 metabolizers with no need for dose adjustment of metoprolol. In extensive metabolizers of dextromethorphan, a substrate of CYP2D6, ranolazine inhibits partially the formation of the main metabolite dextrorphan. OCT2 Substrates In subjects with type 2 diabetes mellitus, the exposure to metformin is increased by 40% and 80% following administration of ranolazine 500 mg twice daily and 1000 mg twice daily, respectively. If co-administered with RANEXA 1000 mg twice daily, do not exceed metformin doses of 1700 mg/day [see Drug Interactions (7.2)]. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Ranolazine tested negative for genotoxic potential in the following assays: Ames bacterial mutation assay, Saccharomyces assay for mitotic gene conversion, chromosomal aberrations assay in Chinese hamster ovary (CHO) cells, mammalian CHO/HGPRT gene mutation assay, and mouse and rat bone marrow micronucleus assays. There was no evidence of carcinogenic potential in mice or rats. The highest oral doses used in the carcinogenicity studies were 150 mg/kg/day for 21 months in rats (900 mg/m2/day) and 50 mg/kg/day for 24 months in mice (150 mg/m2/day). These maximally tolerated doses are 0.8 and 0.1 times, respectively, the daily maximum recommended human dose (MRHD) of 2000 mg on a surface area basis. A published study reported that ranolazine promoted tumor formation and progression to malignancy when given to transgenic APC (min/+) mice at a dose of 30 mg/kg twice daily [see References (15)]. The clinical significance of this finding is unclear. In male and female rats, oral administration of ranolazine that produced exposures (AUC) approximatelty 3-fold or 5-fold higher, respectively, than the MRHD had no effect on fertility. 14 CLINICAL STUDIES 14.1 Chronic Stable Angina CARISA (Combination Assessment of Ranolazine In Stable Angina) was a study in 823 chronic angina patients randomized to receive 12 weeks of treatment with twice-daily RANEXA 750 mg, 1000 mg, or placebo, who also continued on daily doses of atenolol 50 mg, amlodipine 5 mg, or diltiazem CD 180 mg. Sublingual nitrates were used in this study as needed. In this trial, statistically significant (p < 0.05) increases in modified Bruce treadmill exercise duration and time to angina were observed for each RANEXA dose versus placebo, at both trough (12 hours after dosing) and peak (4 hours after dosing) plasma levels, with minimal effects on blood pressure and heart rate. The changes versus placebo in exercise parameters are presented in Table 1. Exercise treadmill results showed no increase in effect on exercise at the 1000 mg dose compared to the 750 mg dose. Table 1 Exercise Treadmill Results (CARISA)  Mean Difference from Placebo (sec) Study CARISA (N=791) RANEXA Twice-daily Dose 750 mg 1000 mg Exercise Duration   Trough 24* 24*   Peak 34† 26* Time to Angina   Trough 30* 26*   Peak 38† 38† Time to 1 mm ST-Segment Depression   Trough 20 21   Peak 41† 35† p-value ≤ 0.05 p-value ≤ 0.005 The effects of RANEXA on angina frequency and nitroglycerin use are shown in Table 2. Table 2 Angina Frequency and Nitroglycerin Use (CARISA) Placebo RANEXA 750 mg RANEXA 1000 mg   Angina Frequency (attacks/week) N 258 272 261 Mean 3.3 2.5 2.1 P-value vs placebo — 0.006 < 0.001 Nitroglycerin Use (doses/week) N 252 262 244 Mean 3.1 2.1 1.8 P-value vs placebo — 0.016 < 0.001 Twice daily Tolerance to RANEXA did not develop after 12 weeks of therapy. Rebound increases in angina, as measured by exercise duration, have not been observed following abrupt discontinuation of RANEXA. RANEXA has been evaluated in patients with chronic angina who remained symptomatic despite treatment with the maximum dose of an antianginal agent. In the ERICA (Efficacy of Ranolazine In Chronic Angina) trial, 565 patients were randomized to receive an initial dose of RANEXA 500 mg twice daily or placebo for 1 week, followed by 6 weeks of treatment with RANEXA 1000 mg twice daily or placebo, in addition to concomitant treatment with amlodipine 10 mg once daily. In addition, 45% of the study population also received long-acting nitrates. Sublingual nitrates were used as needed to treat angina episodes. Results are shown in Table 3. Statistically significant decreases in angina attack frequency (p=0.028) and nitroglycerin use (p=0.014) were observed with RANEXA compared to placebo. These treatment effects appeared consistent across age and use of long-acting nitrates. Table 3 Angina Frequency and Nitroglycerin Use (ERICA)  Placebo RANEXA   Angina Frequency (attacks/week) N 281 277 Mean 4.3 3.3 Median 2.4 2.2 Nitroglycerin Use (doses/week) N 281 277 Mean 3.6 2.7 Median 1.7 1.3 1000 mg twice daily Gender Effects on angina frequency and exercise tolerance were considerably smaller in women than in men. In CARISA, the improvement in Exercise Tolerance Test (ETT) in females was about 33% of that in males at the 1000 mg twice-daily dose level. In ERICA, where the primary endpoint was angina attack frequency, the mean reduction in weekly angina attacks was 0.3 for females and 1.3 for males. Race There were insufficient numbers of non-Caucasian patients to allow for analyses of efficacy or safety by racial subgroup. 14.2 Lack of Benefit in Acute Coronary Syndrome In a large (n=6560) placebo-controlled trial (MERLIN-TIMI 36) in patients with acute coronary syndrome, there was no benefit shown on outcome measures. However, the study is somewhat reassuring regarding proarrhythmic risks, as ventricular arrhythmias were less common on ranolazine [see Clinical Pharmacology (12.2)], and there was no difference between RANEXA and placebo in the risk of all-cause mortality (relative risk ranolazine:placebo 0.99 with an upper 95% confidence limit of 1.22). 15 REFERENCES M.A. Suckow et al. The anti-ischemia agent ranolazine promotes the development of intestinal tumors in APC (min/+) mice. Cancer Letters 209(2004):165−9. 16 HOW SUPPLIED/STORAGE AND HANDLING RANEXA is supplied as film-coated, oblong-shaped, extended-release tablets in the following strengths: 500 mg tablets are light orange, with GSI500 on one side 1000 mg tablets are pale yellow, with GSI1000 on one side RANEXA (ranolazine) extended-release tablets are available in: Strength NDC Unit-of-Use Bottle (60 Tablets) 500 mg 61958-1003-1 Unit-of-Use Bottle (60 Tablets) 1000 mg 61958-1004-1 Store RANEXA tablets at 25°C (77°F) with excursions permitted to 15° to 30°C (59° to 86°F). http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=beb482de-f251-476b-9d38-40577c36f5a3 胸痛新治疗药Ranexa(ranolazine)获美国FDA批准上市 近日，美国FDA批准Ranexa（ranolazine）用于治疗慢性心绞痛的新药。 Ranexa，一个新的分子实体（new molecular entity，NME），是十多年来首个被批准用于治疗慢性心绞痛的药品。尽管ranolazine的几种药理活性已被描述，但还未完全清楚该药确切的作用方式。由于Ranexa会影响心脏内的电导（延长QT间期），所以它只能用于对其他抗心绞痛药品（长效硝酸盐、钙通道阻滞剂和β阻滞剂）无反应的患者。 慢性心绞痛表现为：锻炼期间因心肌不能获得足够的氧气而发生的阵发性胸痛、压迫或不适。心绞痛最常见的原因是冠心病，在冠心病中，给心脏提供富含氧气的血液的冠状动脉被斑块沉淀物所堵塞。据美国心脏协会（According to the American Heart Association）称，每年大约680万美国人被诊断患有心绞痛。尽管这些患者中许多人对其他疗法（包括手术和其它已批准的药品）有响应，但是有些人尽管接受了这些疗法仍然还有心绞痛。心绞痛急性发作是以舌下含服硝酸甘油来治疗，然而慢性心绞痛的治疗药被给予旨在增加一个人于心绞痛发作前所能做的活动量。这常常通过证明心绞痛患者在服用该药时能在跑步机或自行车上锻炼更长时间来进行验证。 “慢性心绞痛限制了人们的活动，”FDA的CDER主任Steven Galson医学博士称。“Ranexa的批准，为尽管使用其他心绞痛药但仍然因心绞痛症状而受苦的美国人提供了一个新的治疗选择。” 有些患者尽管使用其他抗心绞痛药治疗但仍然具有慢性心绞痛症状。Ranexa曾在这些患者中被研究。以下两个临床试验已在进行：Ranolazine在慢性心绞痛中的功效(Efficacy of Ranolazine in Chronic Angina，ERICA)和Ranolazine在稳定型心绞痛中的联合评估 (Combination Assessment of Ranolazine In Stable Angina，CARISA)。在ERICA中，565位虽然服用足够剂量的钙通道阻滞剂，但每周仍然经受大约4.5次心绞痛发作的患者，被随机化分组为Ranexa组或安慰剂组达6周。与安慰剂组相比，接受Ranexa的患者每周大约减少一次心绞痛发作。 在CARISA中，使用某种钙通道阻滞剂或β阻滞剂（atenolol，阿替洛尔）治疗的827位患者，被随机化分组为Ranexa组或安慰剂组达12周，用一种正式的锻炼跑步机检测。Ranexa组的患者平均运动改善量类似于其他抗心绞痛疗法。 在两个研究中，Ranexa看来在女性中的有效性低于男性。 在临床研究中，常见副作用包括晕眩、头痛、便秘和恶心。 Ranexa由加利福尼亚州Palo Alto市的CV Therapeutics公司生产。