dronedarone-FDA说明书

______________________________________________________________________________________________________________________________________________________________________________________________________________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.。

核准日期：2011年12月31日修改日期：2014年02月18日2014年10月31日2016年01月12日2017年01月16日2018年04月28日2018年11月08日2018年11月21日2020年04月07日2020年06月24日2021年XX月XX日雷珠单抗注射液说明书请仔细阅读说明书并在医师指导下使用。

【药品名称】通用名称：雷珠单抗注射液商品名称：诺适得®/Lucentis®英文名称：Ranibizumab Injections汉语拼音：Leizhu Dankang Zhusheye【成份】活性成份：雷珠单抗化学名称：G1，抗-（人血管内皮生长因子）Fab片断（人-鼠单克隆rhuFabV2γ1-链），二硫键结合人-鼠单克隆rhuFabV2κ-链分子量：48KD处方组成：1mL含10mg雷珠单抗。

本品所含辅料为：α,α-海藻糖二水合物；组氨酸；盐酸组氨酸一水合物；聚山梨醇酯20。

【性状】透明至微乳白色液体。

【适应症】雷珠单抗注射液适用于成人:∙用于治疗湿性（新生血管性）年龄相关性黄斑变性（AMD）。

∙用于治疗糖尿病性黄斑水肿（DME）引起的视力损害。

∙用于治疗糖尿病视网膜病变（DR）[增殖性糖尿病视网膜病变（PDR）和中重度至重度非增殖性糖尿病视网膜病变（NPDR）]。

∙用于治疗继发于视网膜静脉阻塞（RVO）（视网膜分支静脉阻塞（BRVO）或视网膜中央静脉阻塞（CRVO））的黄斑水肿引起的视力损害。

∙用于治疗脉络膜新生血管（CNV，即继发于病理性近视（PM）和其它原因的CNV）导致的视力损害。

雷珠单抗注射液适用于早产儿:∙用于治疗I区（1+、2+、3或3+期）、II区（3+期）早产儿视网膜病变（ROP）和AP-ROP（急进性后极部ROP）。

【规格】10mg/mL，每瓶装量0.20mL。

【用法用量】本品应在有资质的医院和眼科医生中使用。

医院应具备疾病诊断和治疗所需的相关仪器设备和条件，眼科医生应具备确诊湿性年龄相关性黄斑变性，糖尿病性黄斑水肿，糖尿病视网膜病变（DR）[增殖性糖尿病视网膜病变（PDR）和中重度至重度非增殖性糖尿病视网膜病变（NPDR）],继发于视网膜静脉阻塞（RVO）的黄斑水肿，脉络膜新生血管疾病以及早产儿视网膜病变的能力和丰富的玻璃体内注射经验。

抗心律失常新药——决奈达隆决奈达隆(Dronedarone)是一种苯并呋喃的衍生物，在结构上与胺碘酮相似，没有碘取代基。

与胺碘酮一样，它表现出所有4种Vaughan-Williams分类药物的抗心律失常特性。

Multaq(决奈达隆，dronedarone)片使用说明书（09年FDA 批准）1. 适应证：决奈达隆是抗心律失常药物，适用于阵发性或持续性心房颤动(AF)患者，降低住院风险。

2. 剂量和用法剂量和用法：每天2 次，早和晚餐各 1 片400mg。

3. 禁忌证：1.心衰类别IV 或最近失代偿症状性心衰；2.II-或III-度房室(A V)阻断或病态窦房结综合征(除使用功能性心脏起搏器)；3.心动过缓50 bpm；4.同时用强CYP3A 抑制剂；5. 同时用延长QT 间隔及可诱发尖端扭转型室性心动过速(Torsade de Pointes)药物和草药；6. QTc Bazett 间隔500 ms；7. 严重肝损伤；8.妊娠；9. 哺乳母亲。

WARNING:INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; MULTAQ doubles the risk of death. MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure.In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure. MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm.1、说明书中已经包含一个黑框警告，内容为禁止将该药用于患有NYHA Ⅳ级心力衰竭或是近期曾发生失代偿而需要住院的患者。

---------------------------------------------------------------最新资料推荐------------------------------------------------------盐酸决奈达隆片中文说明书Multaq(决奈达隆，dronedarone)片使用说明书 2009 年 12 版决奈达隆，决奈达隆片使用说明书批准日期：美国 FDA，2009 年7 月 1 日欧盟EMEA 2009 年12 月16 日；公司：Sanofi-aventis 1.适应证：决奈达隆是抗心律失常药物，适用于阵发性或持续性心房颤动(AF) 适应证：适应证或心房扑动(AFL)患者，减低住院风险，近期 AF/AFL 发作和伴心血管风险因子患者(即年龄&gt;70、高血压、糖尿病、既往心血管意外、左心房直径≥50 mm 或左心室射血分数[LVEF]&lt;40%)，窦性心律或心律可复律的患者。

2 剂量和用法剂量和用法：每天 2 次，早和晚餐各 1 片 400mg。

3 禁忌证：禁忌证： 1.心衰类别 IV 或最近失代偿症状性心衰；2.II-或 III-度房室(AV)阻断或病态窦房结综合征(除使用功能性心脏起搏器)；3.心动过缓&lt;50 bpm；4.同时用强 CYP3A 抑制剂；5. 同时用延长 QT 间隔及可诱发尖端扭转型室性心动过速(Torsade de Pointes)药物和草药；6. QTc Bazett 间隔( )≥500 ms；7. 严重肝损伤；8.妊娠；9. 哺乳母亲。

6 不良反应在说明书中任何处描述担忧下列安全性： 1)新心衰或心衰恶化[见警告和注意事项(5.1)] 2)钾消耗利尿药的低钾血症和低镁血症[见警告和注意事项(5.2)] 3)QT 延长[见警告和注意事项(5.3)] 在 AF 或 AFL 患者每天 2 次 400mg 决奈达隆的安全性评价是基于 5 项安慰剂对照研究，ATHENA，EURIDIS，ADONIS，ERATO1/ 13和 DAFNE。

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use KEPPRA XR safely and effectively. See full prescribing information for KEPPRA XR.KEPPRA XR (levetiracetam) tablet, film coated, extended release for oral useInitial U.S. Approval: 1999RECENT MAJOR CHANGESWarnings and Precautions (5.1)[04/2009] Patient Counseling Information (17)[04/2009]INDICATIONS AND USAGEKEPPRA XR is an antiepileptic drug indicated for adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy (1)DOSAGE AND ADMINISTRATIONTreatment should be initiated with a dose of 1000 mg once daily. Thedaily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg (2).See full prescribing information for use in patients with impaired renal function (2.1).DOSAGE FORMS AND STRENGTHS•500 mg white, film-coated extended-release tablet (3)•750 mg white, film-coated extended-release tablet (3)CONTRAINDICATIONS•None (4)WARNINGS AND PRECAUTIONS•Suicidal Behavior and Ideation. (5.1)•Neuropsychiatric Adverse Reactions: KEPPRA XR causes somnolence, dizziness, and behavioral abnormalities. The adverse reactions that may be seen in patients receiving KEPPRA XR tablets are expected to be similar to those seen in patients receiving immediate-release KEPPRA tablets. (5.2)•In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, immediate-release KEPPRA causes somnolence and fatigue, coordination difficulties, and behavioral abnormalities (e.g., psychotic symptoms, suicidal ideation, and other abnormalities). (5.2)•Withdrawal Seizures: KEPPRA XR must be gradually withdrawn. (5.3)ADVERSE REACTIONS•Most common adverse reactions (difference in incidence rate is ≥5% between KEPPRA XR-treated patients and placebo-treated patients and occurred more frequently in KEPPRA XR-treated patients) include: somnolence and irritability (6.1).To report SUSPECTED ADVERSE REACTIONS, contact UCB, Inc. at 866-822-0068 or FDA at 1-800-FDA-1088 or /medwatchTo report SUSPECTED ADVERSE REACTIONS, contact at or FDA at 1-800-FDA-1088 or /medwatchUSE IN SPECIFIC POPULATIONS•To enroll in the UCB AED Pregnancy Registry call 888-537-7734 (toll free). To enroll in the North American Antiepileptic Drug Pregnancy Registry call (888) 233-2334 (toll free). (8.1)• A dose adjustment is recommended for patients with impaired renal function, based on the patient's estimated creatinine clearance (8.6).See 17 for PATIENT COUNSELING INFORMATION and the FDA-approved Medication GuideRevised: 10/2009FULL PRESCRIBING INFORMATION: CONTENTS *1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Adult Patients With Impaired Renal Function3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Suicidal Behavior and Ideation5.2 Neuropsychiatric Adverse Reactions5.3 Withdrawal Seizures5.4 Hematologic Abnormalities5.5 Hepatic Abnormalities5.6 Laboratory Tests6 ADVERSE REACTIONS6.1 Clinical Studies Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 General Information7.2 Phenytoin7.3 Valproate7.4 Other Antiepileptic Drugs7.5 Oral Contraceptives7.6 Digoxin7.7 Warfarin7.8 Probenecid8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.2 Labor And Delivery8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Use In Patients With Impaired Renal Function9 DRUG ABUSE AND DEPENDENCE10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism Of Action12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility13.2 Animal Toxicology And/Or Pharmacology14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How Supplied16.2 Storage17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEKEPPRA XR™ is indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy.2 DOSAGE AND ADMINISTRATIONTreatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg.2.1 Adult Patients With Impaired Renal FunctionKEPPRA XR dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed. CLcr in mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:[140-age (years)] x weight (kg)CLcr = ---------------------------------------------- x 1 0.8572 x serum creatinine (mg/dL)1. For female patientsThen CLcr is adjusted for body surface area (BSA) as follows:CLcr (mL/min)CLcr (mL/min/1.73m2) = ----------------------------- x 1.73BSA subject (m2)Table 1: Dosing Adjustment Regimen For Adult Patients With Impaired Renal FunctionGroup CreatinineClearance(mL/min/1.73m2) Dosage(mg)FrequencyNormal > 80 1000 to 3000 Every 24 hMild 50 – 80 1000 to 2000 Every 24 h Moderate 30 – 50 500 to 1500 Every 24 h Severe < 30 500 to 1000 Every 24 h3 DOSAGE FORMS AND STRENGTHSKEPPRA XR tablets are white, oblong-shaped, film-coated extended-release tablets imprinted in red with "UCB 500XR" on one side and contain 500 mg levetiracetam.KEPPRA XR tablets are white, oblong-shaped, film-coated extended-release tablets imprinted in red with "UCB 750XR" on one side and contain 750 mg levetiracetam.4 CONTRAINDICATIONSNone5 WARNINGS AND PRECAUTIONS5.1 Suicidal Behavior and IdeationAntiepileptic drugs (AEDs), including KEPPRA XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.Table 2 Risk by indication for antiepileptic drugs in the pooled analysisIndication Placebo Patients withEvents Per 1000 PatientsDrug Patients withEvents Per 1000 PatientsRelative Risk: Incidenceof Events in DrugPatients/Incidence inPlacebo PatientsRisk DifferenceAdditional DrugPatients with Events Per1000 Patients Epilepsy 1.0 3.4 3.5 2.4Psychiatric 5.7 8.5 1.5 2.9Other 1.0 1.8 1.9 0.9Total 2.4 4.3 1.8 1.9The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.Anyone considering prescribing KEPPRA XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.5.2 Neuropsychiatric Adverse ReactionsKEPPRA XR TabletsIn some patients experiencing partial onset seizures, KEPPRA XR causes somnolence, dizziness, and behavioral abnormalities.In the KEPPRA XR double-blind, controlled trial in patients experiencing partial onset seizures, 7.8% of KEPPRA XR-treated patients experienced somnolence compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of KEPPRA XR-treated patients compared to 2.5% of placebo-treated patients.A total of 6.5% of KEPPRA XR-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated patients. Irritability was reported in 6.5% of KEPPRA XR-treated patients. Aggression was reported in 1.3% of KEPPRA XR-treated patients.No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.The number of patients exposed to KEPPRA XR was considerably smaller than the number of patients exposed to immediate-release KEPPRA tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release KEPPRA controlled trials may also occur in patients receiving KEPPRA XR.Immediate-Release KEPPRA TabletsIn controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, immediate-release KEPPRA causes the occurrence of central nervous system adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2) coordination difficulties, and 3) behavioral abnormalities.In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of immediate-release KEPPRA-treated patients reported somnolence, compared to 8.4% of placebo patients. There was no clear dose response up to 3000 mg/day.In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated patients reported asthenia, compared to 9.1% of placebo patients.A total of 3.4% of immediate-release KEPPRA-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients.Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment.In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-release KEPPRA-treated patients experienced psychotic symptoms compared to 1 (0.2%) placebo patient.A total of 13.3% of immediate-release KEPPRA patients experienced other behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.5.3 Withdrawal SeizuresAntiepileptic drugs, including KEPPRA XR, should be withdrawn gradually to minimize the potential of increased seizure frequency.5.4 Hematologic AbnormalitiesAlthough there were no obvious hematologic abnormalities observed in treated patients in the KEPPRA XR controlled study, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients in the immediate-release KEPPRA controlled studies should be considered to be relevant for KEPPRA XR-treated patients.In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release KEPPRA-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts.5.5 Hepatic AbnormalitiesThere were no meaningful changes in mean liver function tests (LFT) in the KEPPRA XR controlled trial. No patients were discontinued from the controlled trial for LFT abnormalities.There were no meaningful changes in mean liver function tests (LFT) in controlled trials of immediate-release KEPPRA tablets in adult patients; lesser LFT abnormalities were similar in drug and placebo-treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.5.6 Laboratory TestsAlthough effects on laboratory tests were not clinically significant with KEPPRA XR treatment, it is expected that the data from immediate-release KEPPRA tablets controlled studies would be considered relevant for KEPPRA XR-treated patients.Although most laboratory tests are not systematically altered with immediate-release KEPPRA treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.6 ADVERSE REACTIONS6.1 Clinical Studies 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.The prescriber should be aware that the adverse reaction incidence figures in the following table, obtained when KEPPRA XR was added to concurrent AED therapy, cannot be used to predict the frequency of adverse experiences in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.KEPPRA XR TabletsIn the well-controlled clinical study using KEPPRA XR in patients with partial onset seizures, the most frequently reported adverse reactions in patients receiving KEPPRA XR in combination with other AEDs, not seen at an equivalent frequency among placebo-treated patients, were irritability and somnolence.Table 3 lists treatment-emergent adverse reactions that occurred in at least 5% of epilepsy patients treated with KEPPRA XR participating in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either KEPPRA XR or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity. Table 3: Incidence (%) Of Treatment-Emergent Adverse Reactions In The Placebo-Controlled, Add-On Study By Body System (Adverse Reactions Occurred In At Least 5% Of KEPPRA XR-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)Body System/ Adverse Reaction KEPPRA XR(N=77)%Placebo(N=79)%Gastrointestinal DisordersNausea 5 3Infections and InfestationsInfluenza 8 4Nasopharyngitis 7 5Nervous System DisordersSomnolence 8 3Dizziness 5 3Psychiatric DisordersIrritability 7 0 Discontinuation Or Dose Reduction In The KEPPRA XR Well-Controlled Clinical StudyIn the well-controlled clinical study using KEPPRA XR, 5.2% of patients receiving KEPPRA XR and 2.5% receiving placebo discontinued as a result of an adverse event. The adverse reactions that resulted in discontinuation and that occurred more frequently in KEPPRA XR-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash and respiratory failure. Each of these adverse reactions led to discontinuation in a KEPPRA XR-treated patient and no placebo-treated patients. Comparison Of Gender, Age And RaceThere are insufficient data for KEPPRA XR to support a statement regarding the distribution of adverse experience reports by gender, age and race.Table 4 lists the adverse reactions seen in the well-controlled studies of immediate-release KEPPRA tablets in adult patients experiencing partial onset seizures. Although the pattern of adverse reactions in the KEPPRA XR study seems somewhat different from that seen in partial onset seizure well-controlled studies for immediate-release KEPPRA tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for KEPPRA XR are expected to be similar to those seen with immediate-release KEPPRA tablets.Immediate-Release KEPPRA TabletsIn well-controlled clinical studies of immediate-release KEPPRA tablets as adjunctive therapy to other AEDs in adults with partial onset seizures, the most frequently reported adverse reactions, not seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection and dizziness.Table 4 lists treatment-emergent adverse reactions that occurred in at least 1% of adult epilepsy patients treated with immediate-release KEPPRA tablets participating in placebo-controlled studies and were numerically more common than in patients treatedwith placebo. In these studies, either immediate-release KEPPRA tablets or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.Table 4: Incidence (%) Of Treatment-Emergent Adverse Reactions In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Reactions Occurred In At Least 1% Of Immediate-Release KEPPRA-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)Body System/ Adverse Reaction Immediate-release KEPPRA(N=769)%Placebo(N=439)%Body as a WholeAsthenia 15 9Headache 14 13Infection 13 8Pain 7 6Digestive SystemAnorexia 3 2Nervous SystemSomnolence 15 8Dizziness 9 4Depression 4 2Nervousness 4 2Ataxia 3 1Vertigo 3 1Amnesia 2 1Anxiety 2 1Hostility 2 1Paresthesia 2 1Emotional Lability 2 0Respiratory SystemPharyngitis 6 4Rhinitis 4 3Cough Increased 2 1Sinusitis 2 1Special SensesDiplopia 2 1In addition, the following adverse reactions were seen in other well-controlled studies of immediate-release KEPPRA tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory impairment, myalgia, personality disorders, pruritus, and vision blurred.6.2 Postmarketing ExperienceIn addition to the adverse reactions listed above for immediate-release KEPPRA tablets [see Adverse Reactions (6.1)], the following adverse events have been identified during postapproval use of immediate-release KEPPRA tablets. Because these events 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. The listing is alphabetized: abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), thrombocytopenia and weight loss. Alopecia has been reported with immediate-release KEPPRA use; recovery was observed in majority of cases where immediate-release KEPPRA was discontinued.7 DRUG INTERACTIONS7.1 General InformationIn vitro data on metabolic interactions indicate that KEPPRA XR is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C max levels achieved within the therapeutic dose range, are neither inhibitors of nor high affinity substrates for human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.Levetiracetam circulates largely unbound (<10% bound) to plasma proteins; clinically significant interactions with other drugs through competition for protein binding sites are therefore unlikely.Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin, valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening with immediate-release KEPPRA tablets in the placebo-controlled clinical studies in epilepsy patients. The following are the results of these studies. The potential for drug interactions for KEPPRA XR is expected to be essentially the same as that with immediate-release KEPPRA tablets.7.2 PhenytoinImmediate-release KEPPRA tablets (3000 mg daily) had no effect on the pharmacokinetic disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were also not affected by phenytoin.7.3 ValproateImmediate-release KEPPRA tablets (1500 mg twice daily) did not alter the pharmacokinetics of valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on exposure to and the excretion of the primary metabolite, ucb L057.7.4 Other Antiepileptic DrugsPotential drug interactions between immediate-release KEPPRA tablets and other AEDs (carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also assessed by evaluating the serum concentrations of levetiracetamand these AEDs during placebo-controlled clinical studies. These data indicate that levetiracetam does not influence the plasma concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of levetiracetam.7.5 Oral ContraceptivesImmediate-release KEPPRA tablets (500 mg twice daily) did not influence the pharmacokinetics of an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of levetiracetam.7.6 DigoxinImmediate-release KEPPRA tablets (1000 mg twice daily) did not influence the pharmacokinetics and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of digoxin did not influence the pharmacokinetics of levetiracetam.7.7 WarfarinImmediate-release KEPPRA tablets (1000 mg twice daily) did not influence the pharmacokinetics of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin did not affect the pharmacokinetics of levetiracetam.7.8 ProbenecidProbenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day, did not change the pharmacokinetics of levetiracetam 1000 mg twice daily. C ss max of the metabolite, ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057. The effect of immediate-release KEPPRA tablets on probenecid was not studied.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. KEPPRA XR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus.Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis). There was no overt maternal toxicity at the doses used in this study.Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (approximately 4 times MRHD on a mg/m2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800 mg/kg/day.When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in this study.Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at oral doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis).Pregnancy RegistriesTo provide information regarding the effects of in utero exposure to KEPPRA XR, physicians are advised to recommend that pregnant patients taking KEPPRA XR enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at the website /.UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes in pregnant women being treated with all UCB antiepileptic drugs including KEPPRA XR. To ensure broad program access and reach, either a healthcare provider or the patient can initiate enrollment in the UCB AED Pregnancy Registry by calling (888) 537-7734 (toll free). 8.2 Labor And DeliveryThe effect of KEPPRA XR on labor and delivery in humans is unknown.8.3 Nursing MothersLevetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from KEPPRA XR, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.8.4 Pediatric UseSafety and effectiveness of KEPPRA XR in patients below the age of 16 years have not been established.8.5 Geriatric UseThere were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of KEPPRA XR in these patients. It is expected that the safety of KEPPRA XR in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release KEPPRA tablets.Of the total number of subjects in clinical studies of immediate-release levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of immediate-release KEPPRA in these patients.A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twice-daily doses of immediate-release KEPPRA tablets for 10 days showed no pharmacokinetic differences related to age alone.Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.8.6 Use In Patients With Impaired Renal FunctionThe effect of KEPPRA XR on renally impaired patients was not assessed in the well-controlled study. However, it is expectedthat the effect on KEPPRA XR-treated patients would be similar to the effect seen in well-controlled studies of immediate-release KEPPRA tablets. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving KEPPRA XR [see Clinical Pharmacology (12.3) and Dosage and Administration (2.1)].Clearance of immediate-release levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance.9 DRUG ABUSE AND DEPENDENCEThe abuse and dependence potential of KEPPRA XR has not been evaluated in human studies.。

美国FDA福迪安一氧化氮片福迪安一氧化氮的7大优势1、美国原装进口采用国际先进配方，结合中国人健康状况而设计，由GMP药厂生产，通过ISO9001国际质量认证、国际食品安全管理体系认证，质量安全有保证。

2、安全无副作用绿色天然产品，纯植物萃取，没有任何毒副作用，服用更放心。

3、、科学配方，保障持续足量产生一氧化氮L—精氨酸是产生一氧化氮的基础物质，可以在L—瓜氨酸和几种关键的抗氧化剂的协同作用下，让人体产生大量的一氧化氮。

福迪安一氧化氮同时含有L—精氨酸和L—瓜氨酸，不仅能使机体稳定，还能很好的发挥对心脑健康的效果。

4、与抗氧化剂合用，保持NO的稳定、延长时效福迪安一氧化氮片含有原花青素、维生素E、维生素C三种超强抗氧化及，能很好的保护已经生成的NO，免除自由基侵扰，最大程度的延长NO活动及有效时间的效果。

5、萃取技术萃取物在生产工艺中的纯化阶段，一般厂家采用“化学断裂键法”脱离无效基团，不但产量低，脱离不彻底，而且还会引入化学杂质。

产生毒副作用。

本品采用生物发酵酶切技术，用限制性内切酶去切割萃取物的DNA片断。

这种酶会识别DNA的双链互补螺旋结构，专一性定向酶切。

不但纯度高，最大限度的脱离无效基团而且安全。

不引入任何杂质。

6、智能吸收途径——等渗跨膜转动提高技术药物在人体吸收的过程中，细胞间的转动可分为被动转运和主动转运两种方式。

被动转动呈浓度梯度转动，不耗能。

主动转运是需要载体及能量的跨膜转运需耗能。

由于NO不稳定性，使它对细胞间的跨膜转运条件要求十分苛刻。

当被动转运不能实现时，如进行主动耗能转运。

就极易破坏其结构而失效。

所以一般产品具有疗效部位的局限性，不能深入细胞组织。

而本技术加入等渗因子，智能识别并调节等渗转运条件。

提升第二信使的跨膜转运速度，使生物利用率高达96%以上，为目前吸收率及利用率最高的产品。

7、L-AC速效缓释技术NO的两大有效成分：L-精氨酸的作用是在机体内生成NO迅速起效。