Multaq Information
Multaq () 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)
Multaq () 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 ()
Multaq () 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.
Multaq () Contraindications
Multaq () is contraindicated in patients with:
Multaq () Warnings And Precautions
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.
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.
In 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 []. Multaq () should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [].
New 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 () .
Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Multaq () in the post-marketing 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.
Small 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.
Multaq () Adverse Reactions
The following safety concerns are described elsewhere in the label:
The 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 Multaq () 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 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.
Photosensitivity 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.
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.
Multaq () Drug Interactions
Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6 . Dronedarone's blood levels can therefore be affected by inhibitors and inducers of CYP 3A, and dronedarone can interact with drugs that are substrates of CYP 3A and CYP 2D6.
Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport.
Pharmacodynamic interactions can be expected with beta-blockers; calcium antagonists and digoxin .
In clinical trials, patients treated with dronedarone received concomitant medications including beta-blockers, digoxin, calcium antagonists (including those with heart rate-lowering effects), statins and oral anticoagulants.
Multaq () Overdosage
In 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.
Multaq () Description
Dronedarone 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 CHNOS, HCl with a relative molecular mass of 593.2. Its structural formula is:
Multaq () is provided as tablets for oral administration.
Each tablet of Multaq () contains 400 mg of dronedarone (expressed as base).
The inactive ingredients are:
Multaq () Nonclinical Toxicology
In studies in which dronedarone was administered to rats and mice for up to 2 years at doses of up to 70 mg/kg/day and 300 mg/kg/day, respectively, there was an increased incidence of histiocytic sarcomas in dronedarone-treated male mice (300 mg/kg/day or 5× the maximum recommended human dose based on AUC comparisons), mammary adenocarcinomas in dronedarone-treated female mice (300 mg/kg/day or 8× MRHD based on AUC comparisons) and hemangiomas in dronedarone-treated male rats (70 mg/kg/day or 5× MRHD based on AUC comparisons).
Dronedarone did not demonstrate genotoxic potential in the in vivo mouse micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA synthesis assay, or an in vitro chromosomal aberration assay in human lymphocytes. S-9 processed dronedarone, however, was positive in a V79 transfected Chinese hamster V79 assay.
In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling at doses ≥10mg/kg (equivalent to 0.12× the MRHD on a mg/m basis).
Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg (equivalent to 1.2× the MRHD on a mg/m basis). There were no reported effects on mating behavior or fertility of male rats at doses of up to 100 mg/kg/day.
Multaq () Clinical Studies
ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.
Initially patients were to be ≥70 years old, or
Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either Multaq () 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).
The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.
Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).
Results are shown in Table 3. Multaq () reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.
Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.
The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 1. The event curves separated early and continued to diverge over the 30 month follow-up period.
Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (
The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see ).
a Determined from Cox regression modelb P-value of interaction between baseline characteristics and treatment based on Cox regression modelc Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil
In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either Multaq () 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.
In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.
Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF 75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.
After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months days for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in
Multaq () How Supplied/storage And Handling
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 in:
Multaq () Patient Counseling Information
[See ]
Multaq () should be administered with a meal. Warn patients not to take Multaq () with grapefruit juice.
If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.
Advise patients to consult a physician if they develop signs or symptoms of heart failure such as acute weight gain, dependent edema, or increasing shortness of breath.
Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) to their physician.
Advise patients to inform their physician of any history of heart failure, rhythm disturbance other than atrial fibrillation or flutter or predisposing conditions such as uncorrected hypokalemia.
Multaq () may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.
Multaq ()
Multaq ()
