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Class ⬇

Antidote (Benzodiazepine Receptor Antagonist)

PREGNANCY RECOMMENDATION:Limited Human Data—Animal Data Suggest Low Risk (Maternal Benefit May Outweigh Embryofetal Risk for Overdose)

BREASTFEEDING RECOMMENDATION:Probably Compatible

Pregnancy Summary ⬆ ⬇

No reports describing the use of flumazenil during the first trimester in humans have been located. Two case reports of use in the third trimester did not show any adverse effects in either infant. The drug will probably cross the placenta, so some fetal exposure will likely occur. However, this limited human pregnancy experience prevents a complete assessment of the embryofetal risk. Animal data did not show any embryofetal toxicity or malformations in two species at doses more than 10 times the RHD. If the indication for flumazenil use is to reverse a benzodiazepine overdose, the maternal benefit will likely outweigh any embryofetal risk. Therefore, flumazenil should not be withheld during pregnancy in this clinical scenario. The drug carries a Boxed Warning regarding an increased association with seizures (most likely due to acute benzodiazepine withdrawal).

Breastfeeding Summary ⬆ ⬇

No reports describing the use of flumazenil during human lactation have been located. The drug will probably be found in human breast milk, so some infant exposure might occur. Flumazenil is absorbed orally, but following first pass through the liver, only about 15% of a dose is bioavailable. IV flumazenil has been given directly to neonates to reverse the sedative effects of diazepam administered to the mother immediately before delivery. If indicated, flumazenil should not be withheld during lactation. If used while breastfeeding, the infant should be monitored for the most commonly reported adult side effects of nausea and agitation (both leading to irritability), flushing, fatigue (lethargy), and vomiting (1). If there is a concern about infant exposure to the drug through breast milk, because of the very short elimination half-life, withholding breastfeeding for 4 to 5 hours after the last dose would significantly minimize any contact.

Reference ⬆

  1. Prescribing Information. Flumazenil. Baxter Healthcare; 2018.
  2. ShibataT, KubotaN, YokoyamaH. A pregnant woman with convulsion treated with diazepam, which was reversed with flumazenil just prior to cesarean section [Japanese]. Masui . 1994;43:572.
  3. StahlMMS, SaldeenP, VingeE. Reversal of fetal benzodiazepine intoxication using flumazenil. Br J Obstet Gynaecol . 1993;100:185-188.
  4. RichardP, AutretE, BardolJ, et al. The use of flumazenil in a neonate. J Toxicol Clin Toxicol . 1991;29:137-140.
  5. DixonJC, SpeidelBD, DixonJJ. Neonatal flumazenil therapy reverses maternal diazepam. Acta Paediatr . 1998;87:225-226.