Antiarrhythmic
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of dronedarone in human pregnancy have been located. Major structural anomalies in two animal species and embryo–fetal death in one species were caused by doses equal to or less than the human dose based on BSA. These data strongly suggest that dronedarone should not be used in the 1st trimester of human pregnancy. The manufacturer states that women of childbearing potential must use effective contraception while taking dronedarone (1). The effects of exposure later in pregnancy are completely unknown.
FETAL RISK SUMMARY
Dronedarone is an oral benzofuran derivative that has antiarrhythmic properties belonging to all four Vaughan–Williams classes. It is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm, or left ventricular ejection fraction <40%), who are in sinus rhythm or who will be cardioverted. Dronedarone is extensively metabolized to a less potent but active metabolite. Further metabolism results in a large number of inactive metabolites. Plasma protein binding of dronedarone and the active metabolite is >98%. The elimination half-life of the parent compound is 13–19 hours (1).
Reproduction studies have been conducted in rats and rabbits. In pregnant rats, doses equal to or greater than the maximum recommended human dose based on BSA (MRHD) resulted in 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, ectrodactyly, syndactyly, and anterior and/or posterior club feet). In pregnant rabbits, a dose that was about half the MRHD (the lowest dose tested) caused an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) (1).
In 2-year studies for carcinogenicity, an increased incidence of histiocytic sarcomas in male mice, mammary adenocarcinomas in female mice, and hemangiomas in male rats were observed. No genotoxic potential was noted in multiple assays. In fertility studies with female rats, a dose 0.12 times the MRHD given before breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling. Doses that were 1.2 times the MRHD were associated with decreased corpora lutea, implantations, and live fetuses. However, doses up to 1.2 times the MRHD had no effect on the mating behavior or fertility of male rats (1).
It is not known if dronedarone and its active metabolite cross the human placenta. The molecular weight of the parent drug (about 557 for the free base) and long elimination half-life suggest that it will cross to the embryo–fetus, although the high plasma protein binding might limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of dronedarone during human lactation have been located. The molecular weight of the parent drug (about 457 for the free base) and long elimination half-life (13–19 hours) suggest that it will cross to the embryo–fetus, although the high plasma protein binding (>98%) of dronedarone and its active metabolite might limit the exposure. The effect of this exposure on a nursing infant is unknown. Adverse reactions that were most common in patients treated with the drug included diarrhea, nausea, abdominal pain, vomiting, dyspeptic signs and symptoms, weakness, and bradycardia (1). If a nursing mother chooses to breastfeed while taking this drug, her infant should be closely observed for these effects.
Reference
1.Product information. Multaq. Sanofi-Aventis, 2009.