Included as part of the PRECAUTIONS section.
Cardiovascular Death In NYHA Class IV Or Decompensated
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 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.
Increased Risk Of Stroke 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 [see Clinical Studies].
MULTAQ should only be initiated in patients in sinus rhythm who are receiving
appropriate antithrombotic therapy [see DRUG INTERACTIONS].
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 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 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.
Cases 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]. 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.
Hypokalemia And Hypomagnesemia With Potassium-Depleting
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.
QT Interval Prolongation
Dronedarone induces a moderate (average of about 10 ms
but much greater effects have been observed) QTc (Bazett) prolongation [see CLINICAL
PHARMACOLOGY and Clinical Studies]. If the QTc Bazett interval is
≥ 500 ms, discontinue MULTAQ [see CONTRAINDICATIONS].
Renal Impairment And Failure
Marked increase in serum creatinine, pre-renal azotemia
and acute renal failure, often in the setting of heart failure [see WARNINGS
AND PRECAUTIONS] 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
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.
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 [see Use In Specific Populations].
Patient Counseling Information
Information for Patients
[See Medication Guide]
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 before stopping
treatment with MULTAQ.
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.
Impairment Of Fertility
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 5X the
maximum recommended human dose based on AUC comparisons), mammary
adenocarcinomas in dronedarone-treated female mice (300 mg/kg/day or 8X MRHD
based on AUC comparisons) and hemangiomas in dronedarone-treated male rats (70
mg/kg/day or 5X 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 0.12X the MRHD on a mg/m² basis).
Corpora lutea, implantations and live fetuses were
decreased at 100 mg/kg (equivalent to 1.2X the MRHD on a mg/m² basis).
There were no reported effects on mating behavior or fertility of male rats at
doses of up to 100 mg/kg/day.
Use In Specific Populations
Pregnancy Category X [see CONTRAINDICATIONS]
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 in rabbits 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/m²basis), 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 a mg/m²basis), 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
Actual animal doses: rat ( ≥ 80 mg/kg/day); rabbit
( ≥ 20 mg/kg)
It 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].
Safety and efficacy in children below the age of 18 years
have not been established.
More 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.
Patients with renal impairment were included in clinical
studies. Because renal excretion of dronedarone is minimal [see CLINICAL
PHARMACOLOGY], no dosing alteration is needed.
Dronedarone 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 and CLINICAL PHARMACOLOGY].