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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.。

度他雄胺FDA说明书

--------------------- DOSAGE FORMS AND STRENGTHS -------------0.5-mg soft gelatin capsules (3) -------------------------------CONTRAINDICATIONS ----------------------- Pregnancy and women of childbearing potential. (4, 5.4, 8.1) Pediatric patients. (4) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 Monotherapy 1.2 Combination With Alpha Adrenergic Antagonist 1.3 Limitations of Use 2 DOSAGE AND ADMINISTRATION 2.1 Monotherapy 2.2 Combination With Alpha Adrenergic Antagonist 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Effects on Prostate-Specific Antigen (PSA) and the Use of PSA in Prostate Cancer Detection 5.2 Increased Risk of High-Grade Prostate Cancer 5.3 Evaluation for Other Urological Diseases 5.4 Exposure of Women—Risk to Male Fetus 5.5 Blood Donation 5.6 Effect on Semen Characteristics 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Cytochrome P450 3A Inhibitors 7.2 Alpha Adrenergic Antagonists 7.3 Calcium Channel Antagonists 7.4 Cholestyramine 7.5 Digoxin 7.6 Warfarin

诺适得说明书

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。

胺碘酮应用指南解读2

不影响室内传导，不显负性肌力
9.药代动力学特点
(1)口服生物利用度50％左右(22-86%) (2)脂溶性分布容积大(60L/kg)，起效一定要给负荷量 (3)经肝P450系统代谢(CYP2C6.、CYP2D6、CYP3A4)，
因此与多种药物相互作用 (4)代谢产物去乙基胺碘酮，活性与母药相似，排出慢 (5)心肌浓度高出血浓度10-50倍 (6)半衰期长13-143天，不要随意频繁调整剂量 (7)基本不经肾脏排除(<1%)，肾功能不全可应用(按常规剂量)
③超过48h AF ACC/AHA/ESC推荐胺碘酮用于AF △MI后不适合用sotalol、Dofetilide △CHF和LVD不适合用Dofetilide △LVH △耐AAD的AF
④用法和剂量
抗凝条件下口服 600-800mg/d 7天 400-600mg/d 7 天
200mg/d维持不转复者电复律
⑥电风暴(多次VT发作需电复律) 由AMI引起、或多形性VT风暴，静注阻滞剂，不控制者加用胺碘酮不间断型VT风暴，静注胺碘酮，不控制者加用阻滞剂
⑦心脏停搏，无脉性VT中应用，配合电复律
(2)中止VT/VF胺碘酮用法用量 ①无脉性VT/VF，电击2-3次不转复，加用胺碘酮300mg (5mg/kg)5%葡萄糖稀释后快速静注，不间断心脏按压，再次电击，相隔10-15min 可追加150mg，复苏后 1mg/min 6h，再0.5mg/min 18h，必要时其间追加，总量2.0克左右/24h。 ②中止持续性VT 胺碘酮150mg+5%葡萄糖稀释10min静注，相隔10-15min 追加150mg，3－4剂不中止者，电复律，复律后1mg/min 6h，0.5mg/min 18h
WPW+AF或AP前传AVRT，胺碘酮应用不是首选

抗心律失常新药——决奈达隆

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。

盐酸决奈达隆片中文说明书

---------------------------------------------------------------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>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]<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<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。

阿扎那韦FDA说明书

Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.4, 6.2) Hepatotoxicity: REYATAZ should be used with caution in patients with hepatic impairment (5.5). Patients with hepatitis B or C infection are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.5, 5.5, 6.3, 6.4, 8.8) Nephrolithiasis has been reported. Consider temporary interruption or discontinuation. (5.6, 6.4) Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.7, 6.4), immune reconstitution syndrome (5.8), and redistribution/accumulation of body fat. (5.9) Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.10) -------------------------------ADVERSE REACTIONS-----------------------------Most common adverse reactions (2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or /medwatch --------------------------------DRUG INTERACTIONS----------------------------Coadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 5.1, 7, 12.3) ------------------------USE IN SPECIFIC POPULATIONS---------------------- Pregnancy: Use only if the potential benefit justifies the potential risk. Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry. (8.1) Nursing mothers should be instructed not to breastfeed due to the potential for postnatal HIV transmission. (8.3) Hepatitis B or C co-infection: Monitor liver enzymes. (5.5, 6.3) Renal impairment: Do not use in treatment-experienced patients with end stage renal disease managed with hemodialysis. (2.4, 8.7) Hepatic impairment: REYATAZ should be used with caution in patients with mild to moderate hepatic impairment. Do not use REYATAZ in patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended. (2.5, 8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling Revised: XX/201X

左乙拉西坦缓释片FDA说明书

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.。

吴卫-Dronedarone-房颤药物治疗新的选择(修改)

ADONIS (American- Australian-African trial with Dronedarone In atrial fibrillation patients for the maintenance of Sinus rhythm)
决奈达隆-EURIDIS
EURIDIS： 77个欧洲单位、612例 AF/AFL病例，随机分入400mg dromedarone Bid组或安慰剂组，随访12个月。
决奈达隆Dronedarone房颤药物治疗新的选择
福建省心血管病研究所吴卫 2009年10月
胺碘酮-局限性
胺碘酮是房颤患者维持窦性心律为限制其临床应用的主要因素。
决奈达隆-药理特性
决奈达隆是胺碘酮的一种非碘基化苯并呋喃衍生物，可降低心外膜、M细胞复极跨膜离散度，减少折返性心律失常的基质。
研究入选心功能 II、III级占
98.1% （Dronedarone ）；95.9%（安慰剂组）
决奈达隆-ANDROMEDA
试验预计随访两年，由于中期分析发现Dronedarone组的死亡率明显高于安慰剂组，试验进行7个月被迫提前终止（受试者中位数随访时间2个月）
Dronedarone 组全因死亡率高于安慰剂组
谢谢！
决奈达隆-EURIDIS、ADONIS
与安慰剂比较，减少AF/AFL复发22%及 27.5%(log-rank test分别为P=0.0138, P=0.017)。
EURIDIS、ADONIS试验联合终点
EURIDIS、ADONIS
EURIDIS研究累积AF复发率
EURIDIS、ADONIS
基线状态
Dronedarone 及安慰剂组均接受较到位的药物治疗

美国FDA福迪安一氧化氮片资料

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。

除颤仪迈瑞D3说明书

BeneHeart D3/D2除颤监护仪Defibrillator/Monitor使用说明书Operator’s Manual说明感谢您购买BeneHeart D2、BeneHeart D3除颤监护仪。

使用产品前，请仔细阅读本使用说明书的内容，以便正确使用该产品。

阅读后请妥善保存本使用说明书，以便需要的时候可以随时查阅。

产品名称：除颤监护仪D2、BeneHeart D3规格型号： BeneHeart产品注册号：国食药监械（准）字2011第3210174号产品标准号： YZB/国4122-2010《除颤监护仪》生产许可证编号：粤食药监械生产许20010352号产品性能结构及组成： BeneHeart D3/D2的附件包括体外除颤电极板、体内除颤电极板、多功能电极片及电缆、心电电缆和导联、心电电极片、脉搏氧饱和度探头及电缆、电池。

生产企业名称：深圳迈瑞生物医疗电子股份有限公司产品适用范围用于对患者进行除颤、起搏以及生命体征监护。

注册地址：深圳市南山区高新技术产业园区科技南十二路迈瑞大厦生产地址：深圳市南山区西丽白芒松白公路东侧百旺信高科技工业园9#、10#、11#、12#、13#本使用说明书发行日期：2011-03知识产权本使用说明书及其对应产品的知识产权属于深圳迈瑞生物医疗电子股份有限公司（以下简称“迈瑞公司”）。

未经迈瑞公司书面同意，任何个人或组织不得复制、修改或翻译本使用说明书的任何部分。

、、、和是迈瑞公司的注册商标或者商标。

声明迈瑞公司对本使用说明书拥有最终解释权。

只有在满足下列全部要求的情况下，迈瑞公司才对产品的安全性、可靠性和性能负责，即：装配操作、扩充、重调、改进和修理均由迈瑞公司认可的专业人员进行；所有维修涉及更换的部件以及配套使用的附件、耗材均是迈瑞公司原配（原装）或经迈瑞公司认可的；有关的电气设备符合国家标准和本使用说明书要求；产品操作按照本使用说明书进行。

(优质)茚达特罗格隆溴铵吸入粉雾剂用胶囊-详细说明书与重点

苛达特罗格隆浸铁吸入粉雾剂用胶囊【成份】本品为复方制剂，其活性成份为马来酸荀达特罗和格隆滨铉。

活性成份：马来酸荀达特罗。

化学名称:（R）-5-[2-（5,6-二乙基二氢荀-2-基氨基）-1-羟乙基]-8-羟基-IH-睫咻-2-酮马来酸盐。

分子式：C24H28N2O3 C4H4O4 分子量:508.56。

O活性成份：格隆溪钺。

化学名称演化3-羟基-Ll-二甲基毗咯烷基-α-环戊基扁桃酸酯。

化学结构式：分子式:C19H28BrNO3 分子量：398.34【性状】本品为透明硬胶囊，内容物为白色至类白色粉末，无可见异物。

【适应症】本品适用于成人慢性阻塞性肺疾病（COPD）（包括慢性支气管炎和肺气肿）患者维持性支气管扩张治疗以缓解症状。

【规格】每粒含马来酸荀达特罗IlOμg （以C24H28N2O3计）和格隆滨镀50μg （以C19H28NO3计）。

【用法用量】用量：推荐剂量为每日一次，每次吸入一粒胶囊的药物，采用随附的药粉吸入器给药。

推荐在每日相同的时间吸入本品。

如果漏吸了某剂药物，请尽快在同一天补吸。

应指导患者不得在一天中用药超过一次剂量。

用法：本品仅用于经口吸入给药，本胶囊不得口服。

胶囊只能采用随附的药粉吸入器给药。

应该指导患者正确地使用本品。

对于呼吸症状未见改善的患者应该询问是否吞咽了药物，而非吸入药物。

请参考本说明书中的药粉吸入器安装和使用说明。

肾功能损害：轻至中度肾损害患者可按推荐剂量使用本品。

重度肾损害或需要透析的终末期肾病患者仅在预期受益大于潜在风险时使用本品（参见【注意事项】和【药代动力学】）。

肝功能损害：轻度至中度肝损害患者可按推荐剂量使用本品。

尚无重度肝损害患者的数据，因此在这些患者中应慎用本品（参见【药代动力学】）。

【不良反应】安全性特征来源于对本品复方制剂以及各单一成份的应用经验。

安全性总结：本品的安全性来自推荐治疗剂量下用药长达15个月的数据。

本品显示出的不良反应与单个成份相似。

说明书-奥美拉唑肠溶片(20mg) 美国 Dexcel Ltd

Blister Label Omeprazole DR Tablets 20 mgAcid reducerPush tablet through foil.Dexcel Ltd.1 Dexcel St. Or Akiva30600, IsraelDo not chew or crush tabletsDo not crush tablets in foodBottle LabelNOT FOR RESALETreats Frequent Heartburn!Occurring 2 or More Days a WeekOmeprazole DelayedRelease Tablets 20 mgAcid Reducer14 TabletsOne 14-day course of treatmentDO NOT USE IF PRINTED SEAL UNDER CAP IS BROKEN OR MISSING Manufactured by:Dexcel® Ltd.1 Dexcel St., Or Akiva30600, IsraelMade in IsraelPatient Package InsertOmeprazole Delayed Release Tablets 20 mgAcid ReducerPlease read all of this package insert before taking Omeprazole Delayed Release Tablets 20 mg.OMEPRAZOLE DELAYED RELEASEomeprazole tablet, delayed releaseProduct InformationProduct T ype HUMAN OTC DRUG Ite m Code (Source)NDC:64861-303 Route of Administration ORALActive Ingredient/Active MoietyIngredient Name Basis of Strength Strength O mepra zo le (UNII: KG60484QX9) (Omeprazo le - UNII:KG60484QX9)Omeprazo le20 mgInactive IngredientsIngredient Name StrengthIngredient Name StrengthCa rna uba Wa x (UNII: R12CBM0EIZ)Ferric O xide Red (UNII: 1K09F3G675)Ferric O xide Yello w (UNII: EX438O2MRT)Hypro mello se (UNII: 3NXW29V3WO)Hypro mello se Aceta te Succina te 12070923 (3 MM2/S) (UNII: 36BGF0E889)La cto se Mo no hydra te (UNII: EWQ57Q8I5X)Etha no la mine (UNII: 5KV86114PT)Pro pylene Glyco l (UNII: 6DC9Q167V3)So dium La uryl Sulfa te (UNII: 368GB5141J)So dium Sta rch Glyco la te Type A Po ta to (UNII: 5856J3G2A2)So dium Stea ra te (UNII: QU7E2XA9TG)So dium Stea ryl Fuma ra te (UNII: 7CV7WJK4UI)Ta lc (UNII: 7SEV7J4R1U)Tita nium Dio xide (UNII: 15FIX9V2JP)Triethyl Citra te (UNII: 8Z96QXD6UM)Product CharacteristicsColor bro wn (bro wnish)Score no sco reShape OVAL (capsule-shaped)Siz e13mmFlavor Imprint Code20ContainsPackaging#Item Code Package Description Marketing Start Date Marketing End Date1NDC:64861-303-0114 in 1 BOTTLE, PLASTIC2NDC:64861-303-0210 in 1 CARTON27 in 1 BLISTER PACK3NDC:64861-303-03 2 in 1 CARTON37 in 1 BLISTER PACKMarketing InformationMarke ting Cate gory Application Numbe r or Monograph Citation Marke ting Start Date Marke ting End Date NDA NDA02203203/01/2008Labeler - Dexcel Ltd. (600534200)EstablishmentName Addre ss ID/FEI Busine ss Ope rationsDexcel Ltd.600534200analysis, label, manufacture, packDexcel Ltd.Revised: 4/2010。

7、复方丹参滴丸FDA试验

运动试验在指南或药物评价原则中的地位（中国）以稳定型劳累性冠心病心绞痛为适应症
的临床试验,应进行运动负荷试验的运动耐
受量及抗心肌缺血效果的评价。
中药、天然药物治疗冠心病心绞痛临床试验技术指导原则（第二稿）
运动试验在指南或药物评价原则中的地位（日本）
对于稳定型劳累性冠心病心绞痛患者

以观察运动负荷试验的运动耐受量（最大运动时间）改善效果，观察抗心肌缺血疗效结果，作为主要评价指标进行有效性评价
分组：
安慰剂组（0mg）、低剂量组（125mg）、高剂量组（187.5mg），每12小时服用一次
疗程：8周合并用药：
除速效的硝酸酯类、β 阻滞剂（1种）或钙通道阻滞剂（1种）外，停用其他治疗心绞痛的药物
20
观察指标（END POINTS）

患者日记卡（patient diary card）：记录每日心绞痛发作次数及速效硝酸酯类使用量运动平板试验（ETTs，exercise treadmill test），分别于第28天（当天服药后1~2h）、第29天（当天服药后11~13h）；第56天（当天服药后1~2h，），第57天（当天服药后11~13h）进行，共4次
15
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充血性心衰史，不稳定心绞痛，严重心瓣膜病，重度高血压，重度贫血，怀疑或已知有动脉夹层，急性心肌炎或心包炎，血栓静脉炎，肺栓塞，或 3个月内心梗史。出血素质，或在使用华法林。起搏器植入者。签署知情同意书前的2周内服用过阿司匹林或他汀类药。怀孕或哺乳者。
16
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运动试验在指南或药物评价原则中的地位（欧洲）

• • •

• • •
短期研究（持续数周）应在可控状态下诱发心绞痛或急性缺血症状即可重复性的定量运动实验是必要的定量运动实验---可以评估患者的运动耐受力中期研究( 持续6 个月) 疗效的标准可以是心绞痛发作的次数,硝酸酯服用的量和/ 或运动耐力硝酸酯服用量的数据应有所保留某些研究运动耐力应系统调查欧洲治疗心绞痛药品临床试验指导原则

丹诺士中文说明书

丹诺士中文说明书
商品名称：丹诺士
商品简介：美国兽医Denosyl犬、猫用肝病治疗肝炎药（肝炎/腹水/黄疸）
用法用量：
口服，采用空腹喂服，在进食1小时前或进食后4小时后喂服，效果更佳；可喂少许水来帮助药物从食道进入胃里。

规格：30S/盒（225mg/s）
功能：
增加细胞膜的通透性
提高肝脏谷胱苷肽水平
抑制肝细胞的死亡和促进其细胞增殖
适用范围：
1、由病毒、细菌、寄生虫及先天引发的各种急、慢性肝炎和相关的黄疸性疾病；
2、在使用能引起毒副反应药物或非处方药物引起的肝脏损伤；
3、肝脏或胆囊手术性疾病的支持治疗；
4、各种代谢性疾病治疗，如：糖尿病、肝脂沉积、肾上腺皮质分泌旺盛等疾病；
5、各创伤性疾病恢复；
6、其它毒素引起肝损伤，如发霉的饲料、有机磷中毒、饲料中铜铁超标等。

注意：
该药必须空腹完整服用，早晚各1粒，服用后2小时内不能喂任何食物，可以喂少许水，不可以弄碎，不可以掰开，不可以咀嚼，不可以溶解，必须空腹完整服用。

用喂药棒或者直接喂。

（本品是肠溶薄膜包衣片，请在店主或兽医指导下服用，治疗期间不可停药或换用其他药物）。

NutramaxDenosyl成分是高纯度，活性S-adenosylmethionine，是目前美国兽医用于治疗各种犬猫肝疾的药物，主要功效是修复受损肝细胞，消除腹水，恢复胆功能正常化，降低黄疸，促进犬猫主动进食。

能在短时间能发挥明显效果，疗程7天，可以有明显效果。

曾挽救数百例曾被兽医宣布可以安乐的猫的生命。

达肝素钠注射液说明书--法安明

资料范本本资料为word版本，可以直接编辑和打印，感谢您的下载达肝素钠注射液说明书--法安明地点：__________________时间：__________________说明：本资料适用于约定双方经过谈判，协商而共同承认，共同遵守的责任与义务，仅供参考，文档可直接下载或修改，不需要的部分可直接删除，使用时请详细阅读内容达肝素钠注射液说明书【药品名称】通用名：达肝素钠注射液商品名：法安明/ Fragmin英文名：Dalteparin Sodium Injection汉语拼音：Dagansuna Zhusheye【成份】1.本品主要成分:达肝素钠,组成:1支单剂量注射器达肝素钠2500IU(抗-Xa) 5000IU(抗-Xa) 7500IU(抗-Xa)氯化钠适量－－注射用水加至0.2ml 加至0.2ml 加至0.3ml效价以低分子量肝素第一国际标准中所描述的国际抗-Xa单位(IU)表示。

分子量：平均分子量为5000。

【性状】本品为无色或淡黄色的澄明液体。

【适应症】治疗急性深静脉血栓。

急性肾功能衰竭或慢性肾功能不全者进行血液透析和血液过滤期间预防在体外循环系统中发生凝血。

治疗不稳定型冠状动脉疾病，如:不稳定型心绞痛和非Q-波型心肌梗死。

预防与手术有关的血栓形成。

【规格】0.2ml:5000IU(抗-Xa)注射液【用法用量】如果需要可通过测定抗-Xa以监测本品的活性。

急性深静脉血栓的治疗达肝素钠可以皮下注射每日一次，也可每日二次。

每日一次用法200IU/kg体重，皮下注射每日一次。

不需要监测抗凝血作用。

每日总量不可超过18000IU。

每日二次用法100IU/kg体重，皮下注射每日二次，该剂量适用于出血风险较高的患者。

通常治疗中无需监测，但可进行功能性抗－Xa测定。

皮下注射后3－4小时取血样，可测得最大血药浓度。

推荐的血药浓度范围为0.5－1.0IU抗－Xa/ml。

用达肝素钠的同时可以立即口服维生素K拮抗剂。

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HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use MULTAQ safely and effectively. See full prescribing information for MULTAQ.MULTAQ (dronedarone) TabletsInitial U.S. Approval: 2009WARNING:INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE ORPERMANENT ATRIAL FIBRILLATIONMULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients (4,5.1, 14.3).MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure. (4, 5.2, 14.4)---------------------------- RECENT MAJOR CHANGES ------------------------- •Contraindications (4), Warnings and Precautions (5.6) 09/2012----------------------------INDICATIONS AND USAGE--------------------------- MULTAQ is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF (1, 14).----------------------DOSAGE AND ADMINISTRATION----------------------- One tablet of 400 mg twice a day with morning and evening meals (2)---------------------DOSAGE FORMS AND STRENGTHS---------------------- 400 mg film-coated tablets (3)-------------------------------CONTRAINDICATIONS------------------------------ •Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored) (Boxed Warning, 4)•Recently decompensated heart failure requiring hospitalization or Class IV heart failure. (Boxed Warning, 4)•Second- or third- degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioningpacemaker) (4)•Bradycardia <50 bpm (4)•Concomitant use of a strong CYP3A inhibitor (4)•Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes (4)•Liver or lung toxicity related to the previous use of amiodarone (4) •Severe hepatic impairment (4)•QTc Bazett interval ≥500 ms (4)•Pregnancy (4, 8.1) and Nursing mothers (4, 8.3)•Hypersensitivity to the active substance or to any of the excipients (4)-----------------------WARNINGS AND PRECAUTIONS------------------------ •Determine cardiac rhythm at least once every 3 months. If AF is detected discontinue MULTAQ or cardiovert (5.2)•Ensure appropriate antithrombotic therapy prior to and throughout MULTAQ use (5.3)•Liver injury: if hepatic injury is suspected, discontinue MULTAQ (5.5) •If pulmonary toxicity is confirmed, discontinue treatment (5.6) •Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range (5.7)•Increase in creatinine: Monitor serum creatinine periodically (5.9) •Teratogen: Women of childbearing potential should use effective contraception while using MULTAQ (5.10)------------------------------ADVERSE REACTIONS------------------------------- Most common adverse reactions (≥2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia (6)To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or/medwatch------------------------------DRUG INTERACTIONS------------------------------- Dronedarone is metabolized by CYP 3A and is a moderate inhibitor ofCYP 3A and CYP 2D6 and has potentially important pharmacodynamic interactions (7)•Class I or III Antiarrhythmics: contraindicated (4, 7.1)•Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor digoxin levels (7.1, 7.3)•Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability (7.1,7.2, 7.3)•Beta-blockers: May provoke excessive bradycardia, Initiate with low dose and increase after ECG verification of tolerability (7.1, 7.3) •CYP 3A inducers: Avoid concomitant use (7.2)•Grapefruit juice: Avoid concomitant use (7.2)•Statins: Avoid simvastatin doses greater than 10 mg daily. Follow label recommendations for concomitant use of other statins with a CYP 3Aand P-gp inhibitor like dronedarone (7.3)•CYP 3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of concomitant drug as neededwhen used with MULTAQ (7.3)•Warfarin: Monitor INR after initiating dronedarone in patients taking warfarin. (7.3)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved Medication Guide.Revised: xx/2013FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION1INDICATIONS AND USAGE2DOSAGE AND ADMINISTRATION3DOSAGE FORMS AND STRENGTHS4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS5.1Cardiovascular Death in NYHA Class IV orDecompensated Heart Failure5.2Cardiovascular Death and Heart Failure in PermanentAF5.3Increased Risk of Stroke in Permanent AF5.4New Onset or Worsening Heart Failure5.5Liver Injury5.6Pulmonary Toxicity5.7Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics5.8QT Interval Prolongation5.9Increase in Creatinine after Treatment Initiation5.10Women of Childbearing Potential6ADVERSE REACTIONS6.1Clinical Trials Experience6.2Postmarketing Experience7DRUG INTERACTIONS7.1Pharmacodynamic Interactions7.2Effects of Other Drugs on Dronedarone7.3Effects of Dronedarone on Other Drugs8USE IN SPECIFIC POPULATIONS8.1Pregnancy8.3Nursing Mothers8.4Pediatric Use8.5Geriatric Use8.6Renal Impairment8.7Hepatic Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.2 Pharmacodynamics12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.3 Developmental Toxicity14 CLINICAL STUDIES14.1 ATHENA14.2 EURIDIS and ADONIS14.3 ANDROMEDA14.4 PALLAS16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION17.1 Information for Patients17.2 Medication Guide*Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATIONWARNING:INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIALFIBRILLATIONIn patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; MULTAQ doubles the risk of death. (14.3) MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. (4, 5.1) In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure. (14.4). MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. (4, 5.2)1 INDICATIONS AND USAGEMULTAQ is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF) [see Clinical Studies (14)].2 DOSAGE AND ADMINISTRATIONThe recommended dosage of MULTAQ is 400 mg twice daily in adults. MULTAQ should be taken as one tablet with the morning meal and one tablet with the evening meal.Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ [see Contraindications (4)].3 DOSAGE FORMS AND STRENGTHSMULTAQ 400 mg tablets are provided as white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and “4142” code on the other side.4 CONTRAINDICATIONSMULTAQ is contraindicated in patients with:•Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) [see Boxed Warning and Warnings and Precautions (5.2)]•Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see Boxed Warning and Warnings and Precautions (5.1)]•Second- or third-degree atrioventricular (AV) block, or sick sinus syndrome (except when used in conjunction with a functioning pacemaker)•Bradycardia <50 bpm•Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see Drug Interactions (7.2)]•Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclicantidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics •Liver or lung toxicity related to the previous use of amiodarone•QTc Bazett inte rval ≥500 ms or PR interval >280 ms•Severe hepatic impairment•Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations(8.1)].•Nursing mothers [see Use in Specific Populations (8.3)]•Hypersensitivity to the active substance or to any of the excipients5 WARNINGS AND PRECAUTIONS5.1 Cardiovascular Death in NYHA Class IV or Decompensated Heart Failure MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death.5.2 Cardiovascular Death and Heart Failure in Permanent AFMULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AF. Patients treated with dronedarone should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in atrial fibrillation (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AF.5.3 Increased Risk of Stroke in Permanent AFIn a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy [see Clinical Studies (14.4)]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [see Drug Interactions (7.3)].5.4 New Onset or Worsening Heart FailureNew onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo controlled study in patients with permanent AF increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction.Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ.5.5 Liver InjuryHepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury. 5.6 Pulmonary ToxicityCases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing setting [see Adverse Reactions (6.2)]. Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.5.7 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics Hypokalemia or hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ.5.8 QT Interval ProlongationDronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see Clinical Pharmacology (12.2) and Clinical Studies (14.1)]. If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ [see Contraindications (4)].5.9 Increase in Creatinine after Treatment InitiationSmall increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine’s tubular secretion. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation. Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen. In most cases, these effects appear to be reversible upon drug discontinuation. Monitor renal function periodically.5.10 Women of Childbearing PotentialPremenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices [see Use in Specific Populations (8.1)].6 ADVERSE REACTIONSThe following safety concerns are described elsewhere in the label:•New or worsening heart failure [see Warnings and Precautions (5.4)]•Liver Injury [see Warnings and Precautions (5.5)]•Pulmonary toxicity [see Warnings and Precautions (5.6)]•Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.7)]•QT prolongation [see Warnings and Precautions (5.8)]6.1 Clinical Trials ExperienceThe safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than PlaceboPhotosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.Table 2: Laboratory data/ECG parameters not necessarily reported as adverse eventsPlacebo MULTAQ400 mg twice daily(N=2875) (N=3282)Early increases in creatinine ≥10%21% 51%(N=2237) (N=2701)QTc prolonged 19% 28%Assessment of demographic factors such as gender or age on the incidence of treatment- emergent adverse events did not suggest an excess of adverse events in any particular sub-group.6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of MULTAQ. Because these reactions are reported voluntarily from a population of an unknown size, it is notalways possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Cardiac: New or worsening heart failure [see Warnings and Precautions (5.4)]Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.Hepatic: Liver Injury [see Warnings and Precautions (5.5)]Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis [see Warnings and Precautions (5.6)]Immune: Anaphylactic reactions including angioedemaVascular: Vasculitis, including leukocytoclastic vasculitis7 DRUG INTERACTIONS7.1 Pharmacodynamic InteractionsDrugs prolonging the QT interval (inducing Torsade de Pointes)Co-administration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of Torsade de Pointes-type ventricular tachycardia [see Contraindications (4), Clinical Pharmacology (12.3)].DigoxinIn the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone vs. placebo groups. [See Clinical Trials (14.3)].Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.Calcium channel blockersCalcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone’s effects on conduction.Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].Beta-blockersIn clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].7.2 Effects of Other Drugs on DronedaroneKetoconazole and other potent CYP 3A inhibitorsConcomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see Contraindications (4), Clinical Pharmacology (12.3)].Grapefruit juicePatients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased [see Clinical Pharmacology (12.3)].Rifampin and other CYP 3A inducersAvoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John’s wort because they decrease exposure to dronedarone significantly [see Clinical Pharmacology (12.3)].Calcium channel blockersVerapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].7.3 Effects of Dronedarone on Other DrugsSimvastatinDronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin [see Clinical Pharmacology (12.3)].Other statinsBecause of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gp inhibitors such as dronedarone. Calcium channel blockersDronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.Beta-blockers and other CYP 2D6 substratesDronedarone increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].P-glycoprotein substratesDigoxinDronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].DabigatranExposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.Other P-gp substrates are expected to have increased exposure when co-administered with dronedarone.WarfarinWhen co-administered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR [see Clinical Pharmacology (12.3)].More patients experienced cli nically significant INR elevations (≥ 5) usually within 1 week after starting dronedarone vs. placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group.Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category X [see Contraindications (4)]MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone was teratogenic in rats at the maximum recommended human dose (MRHD), and inrabbits at half the MRHD. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2 basis), fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). When pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on amg/m2 basis), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis).Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)8.3 Nursing MothersIt is not known whether MULTAQ is excreted in human milk. Dronedarone and its metabolites are excreted in rat milk. During a pre- and post-natal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MULTAQ, discontinue nursing or discontinue the drug [see Contraindications (4)].8.4 Pediatric UseSafety and efficacy in children below the age of 18 years have not been established.8.5 Geriatric UseMore than 4500 patients with AF or AFL aged 65 years or above were included in the MULTAQ clinical program (of whom more than 2000 patients were 75 years or older). Efficacy and safety were similar in elderly and younger patients.8.6 Renal ImpairmentPatients with renal impairment were included in clinical studies. Because renal excretion of dronedarone is minimal [see Clinical Pharmacology (12.3)], no dosing alteration is needed.8.7 Hepatic ImpairmentDronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none with severe impairment. No dosage adjustment is recommended for moderate hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].10 OVERDOSAGEIn the event of overdosage, monitor the patient’s cardiac rhythm and blood pressure. Treatment should be supportive and based on symptoms.It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration). There is no specific antidote available.11 DESCRIPTIONDronedarone HCl is a benzofuran derivative with the following chemical name:N-{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide, hydrochloride.Dronedarone HCl is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol.Its empirical formula is C31H44N2O5 S, HCl with a relative molecular mass of 593.2. Its structural formula is:O(CH2)3 CH3O O(CH2)3NCH3SO2HN(CH2)3CH3(CH2)3CH3,HClMULTAQ is provided as tablets for oral administration.Each tablet of MULTAQ contains 400 mg of dronedarone (expressed as base).The inactive ingredients are:Core of the tablets-hypromellose, starch, crospovidone, poloxamer 407, lactosemonohydrate, colloidal silicon dioxide, magnesium stearate.Coating / polishing of the tablets-hypromellose, polyethylene glycol 6000, titaniumdioxide, carnauba wax.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionThe mechanism of action of dronedarone is unknown. Dronedarone has antiarrhythmic properties belonging to all four Vaughan-Williams classes, but the contribution of each of these activities to the clinical effect is unknown.。