雷诺嗪

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雷诺嗪缓释片说明书(英文)

______________________________________________________________________________________________________________________________________________________________________________________________________________HIGHLIGHTS OF PRESCRIBING INFORMATIONThese 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 Initial U.S. Approval: 2006------------------------INDICATIONS AND USAGE------------------------- Ranexa is 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----------------------------- • Use with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin, nelfinavir) (4, 7.1) • Use with CYP3A inducers (e.g., rifampin, phenobarbital) (4, 7.1) • Use in patients with clinically significant hepatic impairment (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, or potassium channel variants causing prolonged QT interval. (5.1) --------------------------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 /medwatch. ------------------------DRUG INTERACTIONS--------------------------- • CYP3A inhibitors: Do not use Ranexa with strong CYP3A inhibitors. With moderate 3A inhibitors (e.g., diltiazem, verapamil, erythromycin), limit maximum dose of Ranexa to 500 mg twice daily. (7.1) • CYP3A inducers: Do not use Ranexa with CYP3A inducers. (7.1) • P-gp inhibitors (e.g., cyclosporine): May need to lower Ranexa dose based on clinical response. (7.1) • Drugs transported by P-gp or metabolized by CYP2D6 (e.g., digoxin, tricyclic antidepressants): May need reduced doses of these drugs when used with Ranexa. (7.2) See 17 for PATIENT COUNSELING INFORMATION Revised: 09/2010FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Dosing Information 2.2 Dose Modification3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 QT Interval Prolongation 6 A DVERSE REACTIONS6.1 Clinical Trial Experience 7 D RUG INTERACTIONS7.1 Effects of Other Drugs on Ranolazine 7.2 Effects of Ranolazine on Other Drugs 8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Use in Patients with Hepatic Impairment 8.7 Use in Patients with Renal Impairment 8.8 Use in Patients with Heart Failure 8.9 Use in Patients with Diabetes Mellitus 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 N ONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.3 Reproductive Toxicology Studies 14 C LINICAL STUDIES14.1 Chronic Stable Angina 14.2 Lack of Benefit in Acute Coronary Syndrome 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGERanexa 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 ADMINISTRATION2.1 Dosing InformationInitiate 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.Modification2.2 DoseDose 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 diltiazem, verapamil, and other moderate CYP3A inhibitors. Down-titrate Ranexa based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine.3 DOSAGE FORMS AND STRENGTHSRanexa 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 side4 CONTRAINDICATIONSRanexa is contraindicated in patients:•Taking strong inhibitors of CYP3A [see Drug Interactions (7.1)]•Taking inducers of CYP3A [see Drug Interactions (7.1)]•With clinically significant hepatic impairment [see Use in Specific Populations (8.6)]5 WARNINGS AND PRECAUTIONS5.1 QT Interval ProlongationRanolazine blocks I Kr 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, or potassium channel variants resulting in a long QT interval.6 ADVERSE REACTIONS6.1 Clinical Trial ExperienceBecause 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 2,018 patients with chronic angina were treated with ranolazine in controlled clinical trials. Of the patients treated with Ranexa, 1,026 were enrolled in three double-blind, placebo-controlled, randomized studies (CARISA, ERICA, MARISA) of up to 12 weeks duration. In addition, upon study completion, 1,251 patients received treatment with Ranexa in open-label, long-term studies; 1,227 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 2.0% in patients treated with Ranexa and were more frequent than the incidence observed in placebo-treated patients:Cardiac Disorders – bradycardia, palpitationsEar and Labyrinth Disorders – tinnitus, vertigoGastrointestinal Disorders – abdominal pain, dry mouth, vomitingGeneral Disorders and Administrative Site Adverse Events – peripheral edemaRespiratory, Thoracic, and Mediastinal Disorders – dyspneaVascular Disorders – hypotension, orthostatic hypotensionOther (< 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, blurred vision, confusional state, hematuria, 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 Trials (14.2)].Laboratory AbnormalitiesRanexa produces small reductions in hemoglobin A1c. Ranexa is not a treatment for diabetes.Ranexa produces elevations of serum creatinine by 0.1 mg/dL, regardless of previous renal function. 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. The elevated creatinine levels are likely due to a blockage of creatinine’s tubular secretion by ranolazine or one of its metabolites.7 DRUG INTERACTIONS7.1 Effects of Other Drugs on RanolazineRanolazine is primarily metabolized by CYP3A and is a substrate of P-glycoprotein (P-gp).CYP3A InhibitorsDo not use Ranexa with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir. Ketoconazole (200 mg twice daily) increases average steady-state plasma concentrations of ranolazine 3.2-fold [see Contraindications (4)].Limit the dose of Ranexa to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, aprepitant, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products. Diltiazem (180–360 mg daily) and verapamil (120 mg three times daily) increase ranolazine steady-state plasma concentrations about 2-fold [see Dosage and Administration (2.2)].Weak CYP3A inhibitors such as simvastatin (20 mg once daily) and cimetidine (400 mg three times daily) do not increase the exposure to ranolazine in healthy volunteers.P-gp InhibitorsDown-titrate Ranexa based on clinical response in patients concomitantly treated with P-gp inhibitors, such as cyclosporine [see Dosage and Administration (2.2)].CYP3A and P-gp InducersAvoid co-administration of Ranexa and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John’s wort. Rifampin (600 mg once daily) decreases the plasma concentration of ranolazine (1000 mg twice daily) by approximately 95% by induction of CYP3A and, probably, P-gp.7.2 Effects of Ranolazine on Other DrugsIn vitro studies indicate that ranolazine and its O-demethylated metabolite are weak inhibitors of CYP3A, moderate inhibitors of CYP2D6 and moderate P-gp inhibitors.Drugs Transported by P-gpRanexa (1000 mg twice daily) causes a 1.5-fold elevation of digoxin plasma concentrations. The dose of digoxin may have to be adjusted.Drugs Metabolized by CYP2D6Ranexa 750 mg twice daily increased the plasma concentrations of a single dose of immediate-release metoprolol (100 mg), a CYP2D6 substrate, by 1.8-fold. The exposure to other CYP2D6 substrates, such as tricyclic antidepressants and antipsychotics, may be increased during coadministration with Ranexa, and lower doses of these drugs may be required.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CIn animal studies, ranolazine at exposures 1.5 (rabbit) to 2 (rat) times the usual human exposure caused maternal toxicity and misshapen sternebrae and reduced ossification in offspring. These doses in rats and rabbits were associated with an increased maternal mortality rate [see Reproductive Toxicology Studies (13.3)]. There are no adequate well-controlled studies in pregnant women. Ranexa should be used during pregnancy only when the potential benefit to the patient justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether ranolazine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ranolazine in nursing infants, decide whether to discontinue nursing or to discontinue Ranexa, taking into account the importance of the drug to the mother.8.4 Pediatric UseSafety and effectiveness have not been established in pediatric patients.Use8.5 GeriatricOf 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 ranolazine, 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 ImpairmentRanexa is contraindicated in patients with clinically significant hepatic impairment. Plasma concentrations of ranolazine were increased by 30% in patients with mild (Child-Pugh Class A) and by 60% in patients with moderate (Child-Pugh Class B) hepatic impairment. This was not enough to account for the 3-fold increase in QT prolongation seen in patients with mild to severe hepatic impairment [see Contraindications (4)].8.7 Use in Patients with Renal ImpairmentIn patients with varying degrees of renal impairment, ranolazine plasma levels increased up to 50%. The pharmacokinetics of ranolazine has not been assessed in patients on dialysis.8.8 Use in Patients with Heart FailureHeart 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 MellitusA 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 OVERDOSAGEHigh 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.Since ranolazine is about 62% bound to plasma proteins, hemodialysis is unlikely to be effective in clearing ranolazine.11 DESCRIPTIONRanexa (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-(2,6dimethylphenyl)-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:HN N NOHOOMeRanolazine 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 PHARMACOLOGY12.1 Mechanism of ActionThe 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 (I Na). 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 I Kr, which prolongs the ventricular action potential.12.2 PharmacodynamicsHemodynamic EffectsPatients 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 EffectsDose 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 T max 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 plasmaconcentrations, the prolongation of QTc is at least 15 msec. In 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 3,162 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 PharmacokineticsRanolazine 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 C max 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, C max andAUC0-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 DistributionAfter 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 C max and AUC of ranolazine. Therefore, Ranexa may be taken without regard to meals. Over the concentration range of 0.25 to10 μg/mL, ranolazine is approximately 62% bound to human plasma proteins.Metabolism and ExcretionRanolazine 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 twicedaily, 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 InteractionsEffect of other drugs on ranolazineCYP2D6 InhibitorsThe potent CYP2D6 inhibitor, paroxetine (20 mg once daily), increases ranolazine concentrations 1.2-fold. No dose adjustment of Ranexa is required in patients treated with CYP2D6 inhibitors.DigoxinDigoxin (0.125 mg) does not significantly alter ranolazine levels.Effect of ranolazine on other drugsRanolazine and its most abundant metabolites are not known to inhibit the metabolism of substrates for CYP 1A2, 2C8, 2C9, 2C19, or 2E1 in human liver microsomes, suggesting that ranolazine is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes. Drugs Metabolized by CYP3AThe plasma levels of simvastatin, a CYP3A substrate, and its active metabolite are each increased about 2-fold in healthy subjects receiving simvastatin (80 mg once daily) and Ranexa (1000 mg twice daily). Dose adjustments of simvastatin are not required when Ranexa isco-administered with simvastatin.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.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityRanolazine 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) and50 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 maximum recommended human dose (MRHD) of 2 grams 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.13.3 Reproductive Toxicology StudiesAnimal reproduction studies with ranolazine were conducted in rats and rabbits.There was an increased incidence of misshapen sternebrae and reduced ossification of pelvic and cranial bones in fetuses of pregnant rats dosed at 400 mg/kg/day (2 times the MRHD on a surface area basis). Reduced ossification of sternebrae was observed in fetuses of pregnant rabbits dosed at 150 mg/kg/day (1.5 times the MRHD on a surface area basis). These doses in rats and rabbits were associated with an increased maternal mortality rate.14 CLINICAL STUDIES14.1 Chronic Stable AnginaCARISA (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 mgExercise DurationTrough Peak 24*34**24*26*Time to AnginaTrough Peak 30*38**26*38**Time to 1 mm ST-Segment DepressionTrough Peak 2041**2135*** p-value ≤0.05 ** p-value ≤ 0.005The effects of Ranexa on angina frequency and nitroglycerin use are shown in Table 2.Table 2 Angina Frequency and Nitroglycerin Use (CARISA)Placebo Ranexa750 mg aRanexa1000 mg aAngina Frequency (attacks/week) N 258272261 Mean 3.3 2.5 2.1p-value vs placebo — 0.006 <0.001Nitroglycerin Use (doses/week) N 252262244 Mean 3.1 2.1 1.8p-value vs placebo — 0.016 <0.001a Twice dailyTolerance 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 aAngina Frequency (attacks/week) N 281 277 Mean 4.3 3.3 Median 2.4 2.2Nitroglycerin Use (doses/week) N 281 277 Mean 3.6 2.7 Median 1.7 1.3a 1000 mg twice dailyGenderEffects 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.。

心血管疾病治疗药物雷诺嗪的研究进展

同时，雷诺嗪还能够降低心血管疾病患者的住院率和死亡率，延缓疾病的进展。
药物治疗成本效益分析
01
对雷诺嗪在心血管疾病治疗中的成本效益进行分析，需要考虑药物治疗的费用、患者的健康状况以及生活质量等因素。
02
分析结果显示，雷诺嗪在心血管疾病治疗中的成本效益较高，能够有效地降低患者的医疗费用和改善患者的生活质量。
持。
药效评价方法研究
针对雷诺嗪的药效评价，研究者们建立了多种实验模型和方法。通过观察雷诺嗪对心血管功能的影响、对心肌肥厚的抑制作用以及对血液动力学参数的改善等指标，全面评价
雷诺嗪的药效。
药物安全性研究
毒理学研究
为了确保雷诺嗪的安全性，研究者们进行了大量的毒理学研究，包括急性毒性试验、长期毒性试验、生殖毒性试验和致突变试验等。这些研究为评估雷诺嗪的安全剂量范围和治疗窗口提供了重要依据。
03
同时，雷诺嗪还能够减少因心血管疾病导致的生产力损失和社会负担，具有广泛的社会经济效益。
雷诺嗪药物的未来研
04
究方向
新剂型和给药方式研究
纳米制剂
利用纳米技术将雷诺嗪制成纳米药物，以提高药物的生物利用度和靶向性，减少副作用。
口腔速溶片
开发雷诺嗪口腔速溶片，方便患者快速给药，提高用药依从性。
除了心血管疾病外，研究还可以探索雷诺嗪在其他疾病如神经退行性疾病、肿瘤等中的治疗潜力。
THANKS.
合成工艺优化
针对雷诺嗪的合成工艺，研究者们致力于优化反应条件、减少反应步骤和提高产率。通过改进催化剂、溶剂和温度等条件，实现合成过程的绿色化和高效化。
药物药效学研究
药效机制研究
雷诺嗪的药效机制与其抑制Ca2+离子进入细胞有关。研究者们深入探讨雷诺嗪如何通过抑制Ca2+离子进入细胞来发挥治疗心血管疾病的作用，以期为新药研发提供理论支

雷诺嗪药典标准

雷诺嗪药典标准
雷诺嗪（Ranolazine）是一种心血管选择性抗缺血药，其药典标准主要参考美国药典（USP）或者中国药典（Ch.P）中关于雷诺嗪的规定。

以下是雷诺嗪的药典标准概述。

1.品名：雷诺嗪
2.化学名称：5-[2-[[4-[(2-氰基乙基)氨基]苯基]-1,3-二氧杂-2-丙醇]-2-甲基-1,3-二氧杂-2-丙醇
3.分子式：C24H31N3O4
4.分子量：433.51
5.CAS号：95635-55-5
6.外观：白色或类白色结晶性粉末
7.熔点：178-182℃
8.用途：抗心绞痛药
9.制剂：片剂、缓释片剂
10.规格：500mg、1000mg（美国）；375mg、500mg、750mg（英国）
需要注意的是，雷诺嗪的药典标准可能会随着不同国家和地区的药典版本而有所差异。

在实际应用中，应遵循医生开具的处方以及药品说明书上的用法用量。

如有疑问，请咨询专业医生。

手性药物雷诺嗪在Chiralcel OD—H柱上以极性有机相色谱模式的直接拆分

１８
分析仪器
２１年第３００期
业
业
业
；色谱仪器应用专辑ｌ
蒂紊弗恭芥芥芥带芥蒂芥举
手性药物雷诺嗪在ＣｉａｃｌｈｒｌｅＯＤ—Ｈ柱上以极性有机相色谱模式的直接拆分
韩小茜魏燕
（州交通大学。学与生物工程学院，州，３００兰化兰７０７）
甲基苯基氨基甲酸酯）２０；５ｍｍ× ４６．ｍｍｌ粒径Ｄ；
多种色谱模式中使用，通过改变洗脱模式，以使在可某种色谱模式下未能获得对映异构体分离或分离度
较小的样品在另一种色谱模式下获得较好的分离，
的直接拆分还未见文献报道。
１实验部分
１１主要仪器与试剂．
图１手性化合物的结构
１２色谱计算．
死时间（。用１３５三叔丁基苯测定。留￡），，一保
基金项目：肃省科技厅自然科学基金项目资助（２０２２一Ｏ０；肃省科技攻关计划项目资助（ＧＳ６一Ａ５ —０６６；甘３Ｓ４～Ｂ５２）甘２０４２３ —０）兰州交通大
一
同结构、同体积比含量的醇作为极性改性剂时，不样品的保留因子、分离因子、离度呈现不同的变化。分
当改性剂是乙醇时，随乙醇含量的增加，品的保留样因子、分离因子均呈增加趋势，变化不大，离度但分减小；在异丙醇为改性剂时，品的保留因子、离样分因子、离度随异丙醇含量的增加明显增大，甲分在醇／异丙醇一７／０ｖｖ时，离度达到３４；正０３（／）分．０在

雷诺嗪缓释片可减少心绞痛发作频次和硝酸甘油用量

在该项试验中，４％的受试５患者同时服用长效的硝酸酯类药
Ｍａｈｕ博士对此指出，药ｃｏｆ
物抗性的产生不利于抗逆转录病毒的治疗，但由于药物抗性的产生同样亦能削弱病毒的复制能
加拿大的研究人员在近期的
物治疗，且雷诺嗪具有良好的耐
他突变的产生。
（杉菜编译物Ｉ抗性变异的产生可使这些病毒株
显示出更强的毒力。
嗪作为数十年来研发的最新制药技术可适用于心绞痛患者的临床
治疗选择。目前，雷诺嗪已获得美国ＦＡ批准用作慢性心绞痛治疗的Ｄ二线药物，该药具有抗心绞痛和局部缺血治疗作用，且不依赖于
受性。研究人员迄今尚未在雷诺嗪组与安慰剂组间发现严重的不
良反应差异。
力，因此可能具有双重性。一旦患者对药物产生抗性，没必要立即更换药物，但研究人员应密切观察病毒突变的路径。
Ｍａｈｕ最后强调指出，并ｃｏｆ
本文第一作者、来自于美国波士顿ＳｍｅＡＬｖｅ妇女医ａｕｌ．ｅｉｎ院心脏科的Ｐｔｔｅ医生报道ｅｒｏｅＳｎ说，心绞痛发作可为患者及其家庭以及国家医疗保健部门带来巨大的经济负担，而ＥＩＡ研究结ＲＣ果提示雷诺嗪的治疗可为这部分患者带来显著的益处，因为雷诺
研究结果显示，仅有３种逆
维普资讯
绞痛类药物不能达到有效治疗的
患者服用。研究表明女性使用雷

新型抗心绞痛药雷诺嗪的合成分析

新型抗心绞痛药雷诺嗪的合成分析摘要：雷诺嗪是一种新型的抗心绞痛药物，可以通过对心肌能量的代谢进行改善为细胞水平方面起到心肌保护的作用，而且它对血流动力学、血压以及心率都不会造成不良的影响，在临床上有很好地应用前景。

但是它也有一些不良的反应前景，例如头痛、恶心和便秘等。

关键词：抗心绞痛药；雷诺嗪；合成分析引言雷诺嗪是一种用于治疗慢性心绞痛的药物，是一种通过改变脂肪酸和葡萄糖的代谢的抑制脂肪酸部分氧化的抑制剂。

它的化学名为[（士）N-（2，6-二甲基苯基）-4-〔2-经基-3-（2-甲氧基苯氧基）-丙基〕-1-哌嗪-乙酞胺]。

化学式如下图1。

图1 雷诺嗪的化学式它在临床上与其他药物连用或者单独使用都可以安全有效地对慢性心绞痛、充血性心脏病等疾病进行治疗，并且具有不改变血压和心率、不引起血液动力学变化等优点，并且是唯一一种具有这些优点的抗心绞痛的药物[1]。

它的作用机制就是改变对钙离子的吸收，对线粒体内脂肪酸的氧化起到抑制作用，降低细胞对氧的需求（不影响细胞功能），使氧的代谢得到改善，减少释放心脏心肌蛋白以及心肌梗死的面积，起到缓解心绞痛的效果。

1.雷诺嗪的合成方法对于雷诺嗪的合成方法主要有2个：一个是把2，6-二甲基苯胺作为起始的原料，通过酰化反应、缩合发应、环加成和成盐这4步反应过程来合成雷诺嗪。

如下图2。

图2 雷诺嗪合成法1另一个方法就是直接以哌嗪作为原料，经过缩合反应、环加成反应和成盐这几个步骤，最终得到产品雷诺嗪。

过程如下图3。

图3 雷诺嗪合成法2方法1的反应步骤比较长，而且它的总收率比较低，是不适用于工业化生产的，它的优点就是可以不用使用大量地哌嗪。

所以我们选择方法2进行合成分析。

2.实验2.1仪器设备用X4型熔点仪对熔点进行测定，C18硅烷键和硅胶填充柱（250mm×4.5mm，5um），1964B型ESI-MS质谱仪（美国安捷伦），ZF-6型三用紫外线分析仪，其他试剂为分析纯。

雷诺嗪合成药物的制备

公司目前主营产品包括阿达帕林、氨曲南、那氟沙星，曲司氯铵，普卢利沙星，消旋卡多曲，罗沙替丁，以及盐酸去甲托品醇、盐酸去甲托品酮等托品类中间体等几十种医药原料药，中间体等新产品。此外，公司还协助国内医药化工企业开拓国际市场，提供产品代理和技术服务。热忱欢迎国内外客户携手合作，共同发展。业务范围：1.自主开发、生产和销售医药原料和中间体。2.定制开发和生产医药原料和中间体。3.为跨国公司和中小企业开展在中国的采购业务。4.提供医药原料和中间体的资讯和技术服务。
上述文献路线基本上概括了雷诺嗪的合成方法，其中路线（2）具有较大的优势，但缺点是哌嗪没有保护，易生成对称二取代产物，使原料的消耗量增大，成本升高。为此本合成参考合成路线二，设计了如下合成路线，并对合成工艺进行了系统优化。本合成路线在合成单取代哌嗪（5）时，采用哌嗪二盐酸盐与等摩尔哌嗪反应生成的哌嗪单盐前的抗心绞痛药物联合使用可以显著减少心绞痛的发作次数，而且对患者的血压只有轻微的影响，可能成为现有抗心绞痛治疗药物的重要补充。这项试验结果在2001年11月美国阿纳海姆召开的美国心脏病学会科学会议上公布。现在该药物正等待FDA的批准，如果获批，将成为近20年来第一个新类型的抗心绞痛药物。
2000年12月，CV Therapeutics公司宣布开始一项治疗NYHA III或IV级充血性心力衰竭的II 期临床试验。雷诺嗪的作用机制被认为是通过将能量代谢由脂肪酸氧化转为葡萄糖氧化而改善心肌代谢。雷诺嗪还有一种缓释剂型，CV Therapeutics公司正在与Catalytica制药公司进行谈判生产该剂型并进行临床试验。1995年12月，桔生制药公司与罗氏制药公司签定了合作协议，桔生公司拥有在亚洲（包括日本）开发和上市该药物的独家权利。在1996年4 月，CV Therapeutics从罗氏公司手中购买了雷诺嗪在北美和欧洲的开发和上市权。1999年5月，CV Therapeutics公司与Innovex（Quintiles）公司签定了合作协议，共同完成雷诺嗪在美国的商业化经营。

雷诺嗪杂质整理

雷诺嗪相关杂质整理列表中文名英文名CAS号规格纯度结构式雷诺嗪杂质1 RanolazineImpurity 1N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质2 RanolazineImpurity 2N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质3 RanolazineImpurity 3333749-57-810mg-25mg-50mg-100mg ≥99%雷诺嗪杂质4 RanolazineImpurity 4N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质5 RanolazineImpurity 5N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质6 RanolazineImpurity 6N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质7 RanolazineImpurity 75294-61-1 10mg-25mg-50mg-100mg ≥99%湖北扬信医药科技有限公司经营上万种杂质对照品（优势供应硫酸羟氯喹杂质、硝苯地平杂质、沙丁胺醇杂质、达格列净杂质、厄贝沙坦杂质、阿莫西林克拉维酸钾杂质、利伐沙班杂质、阿托伐他汀钙杂质、西格列汀杂质、利格列汀杂质、、舒更葡糖钠杂质、普乐沙福杂质、紫杉醇杂质、卡前列素杂质、替罗非班杂质、特地唑胺杂质、阿哌沙班杂质、泮托拉唑杂质、叶酸杂质、艾地骨化醇杂质、他克莫司杂质、氯雷他定杂质、尼可地尔杂质等），并代理销售中检所、STD、LGC、TLC、EP、USP、TRC等多个品牌产品，提供上万种标准品对照品，真诚为您服务。

雷诺嗪杂质8 RanolazineImpurity 8N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质9 RanolazineImpurity 9N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质优势供应————10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质10 RanolazineImpurity 10N/A 10mg-25mg-50mg-100mg ≥99%雷诺嗪杂质11 RanolazineImpurity 111393717-45-710mg-25mg-50mg-100mg ≥99%雷诺嗪杂质12 RanolazineImpurity 121393717-46-810mg-25mg-50mg-100mg ≥99%。

心血管疾病治疗药物雷诺嗪的研究进展【23页】

Back
安全性评价
• 雷诺嗪通常具有良好耐受性，临床试验中显示出可靠的安全性。
• 最常见的不良反应是头痛、眩晕、疲乏、便秘。肝功、肾功及其他检查未发现明显异常, 对心率和血压均无影响。
展望
• 心血管疾病在中国是威胁人们健康的头号疾病，虽然有很多针对心血管治疗这方面的药物，但是想让人类摆脱心血管疾病的困扰，还需要进一步深入的临床研究。雷诺嗪作为新型抗心绞痛药物，具有全新的作用机理，是唯一对血压、心率等血流动力学无明显影响的抗缺血药物，显示了其独有的抗缺血的优越性，并可与其它抗心绞痛药联合应用并且不会使心脏功能进一步损害。雷诺嗪为临床有效治疗心绞痛、心力衰竭、心律失常和其他心血管疾病提供了新的策略。有报道说明抗心绞痛药物雷诺嗪在控制糖尿病病人血糖方面也存在着一定的潜力。因此，随着临床研究的进一步深入，雷诺嗪在心血管疾病治疗中会得到越来越广泛的应用，具有良好的市场前景。
• 最常见的原因：冠状动脉粥样硬化，临床 90％以上与此有关，又称冠心病，也叫缺
血性心脏病。相对缺血缺氧亦可引起。
心绞痛给人们日常生活带来的不便时时可见
雷诺嗪
• 雷诺嗪[ ranolazine]是 2006年1月由美国食品药品管理局(FDA)批准的治疗慢性心绞痛新药，由CV Ther2apeutics 公司开发研制，商品名 Ranexa，该药为口服缓释片。其化学结构式见图1。
2011(3): 第200-203页. • [10]. Reddy, B.M., H.S. Weintraub and A.Z. Schwartzbard, Ranolazine: a new approach to
treating an old problem. Tex Heart Inst J, 2010. 37(6): p. 641-7.

新型抗心绞痛药物雷诺嗪的研究进展

药理研究
ＺｈａｏＧ等人实验发现雷诺嗪既不会影响心率，也不调节血液动力状态或增加冠状动脉血流量。ＡｎｔｚｅｌｅｖｉｔｃｈＣ等人发现，雷诺嗪是
１８中国处方药２００７．１０Ｎｏ．６７
新药指南
晚钠离子的选择性抑制剂。在离体的心肌细胞中，晚钠离子病理性增加，雷诺嗪可以防止或逆转其导致的机能失常，改善心室复极化的异常情况。ＧｒａｌｉｎｓｋｉＭＲ通过研究发现，雷诺嗪能防止肌原纤维结构紊乱和Ｚ带的模糊，并能减轻线粒体嵴及膜损伤。ＺａｃｈａｒｏｗｓｋｉＫ等研究发现雷诺嗪能显著降低心肌梗死面积和肌钙蛋白Ｔ的释放。
目前雷诺嗪的具体作用机制仍不清楚。起初，人们认为它主要是通过抑制脂肪酸 β－氧化，增加丙酮酸脱氢酶（ＰＤＨ）活性，从而使另一能量来源— ——葡萄糖氧化增加。由于每摩尔氧耗葡萄糖产生的三磷酸腺苷（ＡＴＰ）摩尔数比脂肪酸高１２％，因而提高了心肌在缺血缺氧时氧的利用率。然而，在临床试验中发现，只有当 Байду номын сангаас 药浓度超过治疗浓度（＞１０ μｍｏｌ／Ｌ）才会显示出这种药理作用。所以以前假设的作用机制似乎不能
临床应用及不良反应
Ｒａｎｅｘａ（商品名）为薄膜包衣长方形的缓释片，有两种规格，含雷诺嗪５００ｍｇ的鲜橙色片及含雷诺嗪１０００ｍｇ的淡黄色片。开始应该服用５００ｍｇ／次，日两次，再根据临床症状提高到１０００ｍｇ／次。使用雷诺嗪时，如果同时服用系ＨＭＧ辅酶Ａ还原酶
新型抗心绞痛药物雷诺嗪的研究进展
□ 广东药学院药科学院张浩梁可曹蕾朱尔佳谭载友＊
心绞痛是冠心病中较为常见的类型。在我国，随着生活方式的改变以及生活节奏的加快，心绞痛的发病率逐年增高。目前仍呈上升趋势，已接近欧美国家水平。目前广泛应用于缺血性心脏病的药物包括硝酸酯类、肾上腺素能受体阻滞剂、钙通道拮抗剂等，这些药物都是通过减慢心率、降低血压或削弱心脏泵血功能，从而使心脏做功减少以缓解心绞痛症状。然而，这些药物会对已经衰弱的心脏功能产生进一步损害。因此，研究人员一直致力于寻找其他更有效而副作用少的途径来改善心肌缺血。