Important Safety Information for MULTAQ® (dronedarone)
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 these patients.
MULTAQ is contraindicated in patients in atrial fibrillation (AFib) who will not
or cannot be cardioverted into normal sinus rhythm. In patients with permanent AFib,
MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure.
MULTAQ is also contraindicated in patients:
- With second- or third-degree atrioventricular (AV) block or sick sinus syndrome
(except when used in conjunction with a functioning pacemaker), bradycardia <50
bpm, QTc Bazett interval ≥500 ms or PR interval >280 ms
- Who are or may become pregnant (Category X) or nursing. MULTAQ may cause fetal harm
when administered to a pregnant woman
- With concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole,
voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir,
or drugs or herbal products that prolong the QT interval and might increase the
risk of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants,
certain oral macrolide antibiotics, and Class I and III antiarrhythmics
- With liver or lung toxicity related to the previous use of amiodarone
- With severe hepatic impairment
- With hypersensitivity to the active substance or to any of the excipients
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.
Cardiovascular Death and Heart Failure in Permanent AFib
MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure
events in patients with permanent AFib. Patients treated with MULTAQ should undergo
monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients
who are in AFib (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no
benefit in subjects in permanent AFib.
Increased Risk of Stroke in Permanent AFib
In a placebo-controlled study in patients with permanent AFib, 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
New Onset or Worsening Heart Failure
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 AFib, 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 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. 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.
Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been
reported in patients treated with MULTAQ in the post-marketing setting. 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
Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics
Hypokalemia and 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.
QT Interval Prolongation
MULTAQ induces a moderate (average of about 10 ms but much greater effects have
been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is ≥500 ms,
Renal Impairment and Failure
Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
Small increases in creatinine levels (about 0.1 mg/dL) following MULTAQ 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.
Women of Childbearing Potential
Premenopausal 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.
- Treatment with Class I or III antiarrhythmics or drugs that are strong inhibitors
of CYP 3A must be stopped before starting MULTAQ (see Contraindications)
- Patients should be instructed to avoid grapefruit juice beverages while taking MULTAQ
- Calcium channel blockers with depressant effects and beta-blockers could increase
the bradycardia effects of MULTAQ on conduction
- In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS
(patients with permanent AFib) trials, baseline use of digoxin was associated with an
increased risk of arrhythmic or sudden death in MULTAQ-treated patients compared to placebo.
In patients not taking digoxin, no difference in risk of sudden death was observed
in the MULTAQ vs placebo groups
Digoxin can potentiate the electrophysiologic effects of MULTAQ (such as decreased AV-node conduction).
MULTAQ increases exposure to digoxin
Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin,
monitor serum levels closely, and observe for toxicity
- Postmarketing cases of increased INR with or without bleeding events have been reported
in warfarin-treated patients initiated with MULTAQ. Monitor INR after initiating
MULTAQ in patients taking warfarin
- Statins: Avoid simvastatin doses greater than 10 mg daily. Follow statin label recommendations
for use with CYP 3A and P-gP inhibitors such as MULTAQ
In studies, the most common adverse reactions observed with MULTAQ were diarrhea,
nausea, abdominal pain, vomiting, and asthenia.