HIGHLIGHTS OF PRESCRIBING INFORMATION
The highlights do not include all the information needed to u MULTAQ safely and effectively. See full prescribing information for MULTAQ.
MULTAQ (dronedarone) Tablets
Initial U.S. Approval: 2009
WARNING:
INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR
PERMANENT ATRIAL FIBRILLATION
MULTAQ 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 the 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 ud in conjunction with a functioning
pacemaker) (4)
•Bradycardia <50 bpm (4)
•Concomitant u of a strong CYP3A inhibitor (4)
•Concomitant u 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 u of amiodarone (4) •Severe hepatic impairment (4)•QTc Bazett interval ≥500 ms (4)
•Pregnancy (4, 8.1) and Nursing mothers (4, 8.3)雅思范文
•Hypernsitivity 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 u (5.3)
•Liver injury: if hepatic injury is suspected, discontinue MULTAQ (5.5) •If pulmonary toxicity is confirmed, discontinue treatment (5.6) •Hypokalemia and hypomagnemia: Maintain potassium and magnesium levels within the normal range (5.7)
•Increa in creatinine: Monitor rum creatinine periodically (5.9) •Teratogen: Women of childbearing potential should u effective contraception while using MULTAQ (5.10)
------------------------------ADVERSE REACTIONS------------------------------- Most common adver reactions (≥2%) are diarrhea, naua, 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
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-----------------------------DRUG INTERACTIONS------------------------------- Dronedarone is metabolized by CYP 3A and is a moderate inhibitor of
CYP 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 do of digoxin before treatment and monitor digoxin levels (7.1, 7.3)
•Calcium channel blockers (CCB): Initiate CCB with low do and increa after ECG verification of tolerability (7.1,7.2, 7.3)
•Beta-blockers: May provoke excessive bradycardia, Initiate with low do and increa after ECG verification of tolerability (7.1, 7.3) •CYP 3A inducers: Avoid concomitant u (7.2)
•Grapefruit juice: Avoid concomitant u (7.2)
•Statins: Avoid simvastatin dos greater than 10 mg daily. Follow label recommendations for concomitant u of other statins with a CYP 3A
and 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 needed
when ud 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.
Revid: xx/2013
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION
1INDICATIONS AND USAGE
2DOSAGE AND ADMINISTRATION
fitwell3DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS
5WARNINGS AND PRECAUTIONS
5.1Cardiovascular Death in NYHA Class IV or
Decompensated Heart Failure
5.2Cardiovascular Death and Heart Failure in Permanent
AF
5.3Incread Risk of Stroke in Permanent AF
5.4New Ont or Worning Heart Failure
5.5Liver Injury
5.6Pulmonary Toxicity
5.7Hypokalemia and Hypomagnemia with Potassium-
如何提高幽默感Depleting Diuretics
5.8QT Interval Prolongation
5.9Increa in Creatinine after Treatment Initiation
5.10Women of Childbearing Potential
6ADVERSE REACTIONS
6.1Clinical Trials Experience
6.2Postmarketing Experience
7DRUG INTERACTIONS
7.1Pharmacodynamic Interactions
7.2Effects of Other Drugs on Dronedarone
7.3Effects of Dronedarone on Other Drugs
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.3Nursing Mothers
8.4Pediatric U
8.5Geriatric U
8.6Renal Impairment
8.7Hepatic Impairment
10 OVERDOSAGEftaap
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.3 Developmental Toxicity
14 CLINICAL STUDIES
14.1 ATHENA
14.2 EURIDIS and ADONIS
14.3 ANDROMEDA
14.4 PALLAS
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information for Patients
17.2 Medication Guide
*Sections or subctions omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
WARNING:
INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL
现在FIBRILLATION
In 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 i
n 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 USAGE
MULTAQ 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) [e Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
The 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 [e Contraindications (4)].
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3 DOSAGE FORMS AND STRENGTHS
MULTAQ 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 CONTRAINDICATIONS
MULTAQ is contraindicated in patients with:
•Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) [e Boxed Warning and Warnings and Precautions (5.2)]
•Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [e Boxed Warning and Warnings and Precautions (5.1)]
•Second- or third-degree atrioventricular (AV) block, or sick sinus syndrome (except when ud in conjunction with a functioning pacemaker)
•Bradycardia <50 bpm
•Concomitant u of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [e Drug Interactions (7.2)]
怎样快速学会韩语•Concomitant u of drugs or herbal products that prolong the QT interval and might increa the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic
antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics •Liver or lung toxicity related to the previous u of amiodarone
chine simplified•QTc Bazett inte rval ≥500 ms or PR interval >280 ms
•Severe hepatic impairment
•Pregnancy (Category X): MULTAQ may cau fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is ud during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprid of the potential hazard to a fetus [e U in Specific Populations
(8.1)].
•Nursing mothers [e U in Specific Populations (8.3)]
•Hypernsitivity to the active substance or to any of the excipients
5 WARNINGS AND PRECAUTIONS
5.1 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 becau it doubles the risk of death.
5.2 Cardiovascular Death and Heart Failure in Permanent AF
MULTAQ 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 Incread Risk of Stroke in Permanent AF
In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an incread risk of stroke, particularly in the first two weeks of therapy [e Clinical Studies (14.4)]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appro
priate antithrombotic therapy [e Drug Interactions (7.3)].
5.4 New Ont or Worning Heart Failure
New ont or worning of heart failure has been reported during treatment with MULTAQ in the postmarketing tting. In a placebo controlled study in patients with permanent AF incread rates of heart failure were obrved in patients with normal left ventricular function and no history of symptomatic heart failure, as well as tho with a history of heart failure or left ventricular dysfunction.
Advi 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 worns and requires hospitalization, discontinue MULTAQ.
新闻编辑室第一季5.5 Liver Injury
Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing tting. Advi patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, naua, vomiting, fever,
malai, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic rum enzymes, especially during the first 6 months of treatment, but it is not known whether routine periodic monitoring of rum enzymes will prevent the development of vere liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test rum enzymes, aspartate aminotransfera (AST), alanine aminotransfera (ALT) and alkaline phosphata, as well as rum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cau. Do not restart MULTAQ in patients without another explanation for the obrved liver injury. 5.6 Pulmonary Toxicity
Cas of interstitial lung dia including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing tting [e Adver Reactions (6.2)]. Ont 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 Hypomagnemia with Potassium-Depleting Diuretics Hypokalemia or hypomagnemia 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 Prolongation
Dronedarone induces a moderate (average of about 10 ms but much greater effects have been obrved) QTc (Bazett) prolongation [e Clinical Pharmacology (12.2) and Clinical Studies (14.1)]. If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ [e Contraindications (4)].
5.9 Increa in Creatinine after Treatment Initiation
Small increas 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 cretion. The elevation has a rapid ont, reaches a plateau after 7 days and is reversible after discontinuation. Larger increas in creatinine after dronedarone initiation have been reported in the postmarketing tting. Some cas also reported increas in blood urea nitrogen. In most cas, the effects appear to be reversible upon drug discontinuation. Monitor renal function periodically.
5.10 Women of Childbearing Potential
Premenopausal women who have not undergone a hysterectomy or oophorectomy must u effective contraception while using MULTAQ. Dronedarone caud fetal harm in animal studies at do
s equivalent to recommended human dos. Counl women of childbearing potential regarding appropriate contraceptive choices [e U in Specific Populations (8.1)].
6 ADVERSE REACTIONS
The following safety concerns are described elwhere in the label:
•New or worning heart failure [e Warnings and Precautions (5.4)]
•Liver Injury [e Warnings and Precautions (5.5)]
•Pulmonary toxicity [e Warnings and Precautions (5.6)]
•Hypokalemia and hypomagnemia with potassium-depleting diuretics [e Warnings and Precautions (5.7)]
•QT prolongation [e Warnings and Precautions (5.8)]
6.1 Clinical Trials Experience
The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is bad on 5 pla
cebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In the studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ
传奇 英文版400 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 becau of adver 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 adver reactions obrved with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, naua, abdominal pain, vomiting, and asthenia.
Table 1 displays adver reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, prented by system organ class and by decreasing order of frequency. Adver laboratory and ECG effects are prented parately in Table 2.
