Central Stimulant
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of doxapram in human pregnancy have been located. The animal data are limited but do not suggest a major risk for the embryo and/or fetus. Moreover, although the elimination half-life of the drug is unknown, the duration of effect is very short and the agent is extensively metabolized. Thus, the embryo and/or fetal exposure are probably limited except when continuous infusions are administered. The commercial product contains 0.9% benzyl alcohol as a preservative. Since benzyl alcohol can cross the placenta, the use of doxapram near term, especially continuous infusions, should be avoided because of the potential for toxicity in the newborn. However, if indicated, the maternal benefit from single injections of doxapram at any time in pregnancy appears to outweigh the unknown embryo–fetal risk.
FETAL RISK SUMMARY
Doxapram is a short-acting respiratory stimulant. It is administered IV to stimulate respiration in acute situations such as postanesthesia, mild-to-moderate respiratory and central nervous system depression due to drug overdosage, and hypercapnia in patients with chronic obstructive pulmonary disease. The duration of effect varies from 5 to 12 minutes (1). Doxapram is extensively metabolized by the liver after IV injection (2).
Reproduction studies have been conducted in mice and rats. In rats, doses up to 1.6 times the human dose revealed no evidence of impaired fertility or fetal harm. The dose, assumed to be based on weight, was given by the IM and oral routes, but the human dose (either a single dose of 1–2 mg/kg, or an IV infusion of 1–3 mg/kg/hr) are given IV (1). In another study, no teratogenicity was observed in rats (3). In pregnant mice, a dose of 144 mg/kg/day was given intraperitoneal during organogenesis (4). No gross defects were observed, but fetal death and growth restriction were noted. In addition, minor skeletal defects occurred in the fetuses of one pregnancy (4).
Doxapram crosses the sheep placenta and stimulates fetal breathing (5). Doxapram was infused into a maternal vein over 2–5 minutes and peak fetal plasma levels occurred between 0.08 and 0.17 hours after the start of the infusion. The increase in fetal breathing, up to about 41% during the infusion, was dose related (5).
It is not known if doxapram crosses the human placenta. The drug does cross the placenta in dogs (1) and sheep (5). The molecular weight of the free base (about 379) is low enough for transfer, but the very short duration of action suggests that limited amounts will be available at the maternal:fetal interface after single injections. However, continuous infusions of doxapram probably allows for placental passage to the embryo–fetus.
In an in vitro study, doxapram was shown to undergo substantial metabolism by the human fetal liver (6). The fetal livers were obtained from elective abortions conducted at 10–20 weeks’ gestation.
BREASTFEEDING SUMMARY
No reports describing the use of doxapram during human lactation have been located. In addition, the indications for the drug suggest that such reports will be rare. However, doxapram has been given to newborns at risk for respiratory depression when narcotic analgesics or general anesthetics were used during delivery (7). No adverse effects attributable to doxapram were observed. The molecular weight of the free base (about 379) suggests that the drug will be excreted into breast milk. The maternal plasma elimination half-life is unknown, but the relatively short duration of effect combined with the extensive hepatic metabolism, probably indicates a short half-life, at least for the parent compound. Of note though, doxapram is a basic drug and accumulation in the relatively acidic breast milk by ion trapping is a potential concern, especially if continuous infusions are used. An additional concern involves benzyl alcohol, the preservative used in the commercial preparation that is known to be toxic in newborns.
References
1.Product information. Dopram. A. H. Robins, 1986.
2.Parfitt K, ed. Martindale. The Complete Drug Reference. 32nd ed. London, UK: Pharmaceutical Press, 1999:1480.
3.Imai K. Effect of Doxapram hydrochloride administered to pregnant rats on pre- and post-natal development of their offspring. Oyo Yakuri 1974;8:237–43. As cited by Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:186.
4.Imai K. Effect of Doxapram hydrochloride administered to pregnant mice on pre- and post-natal development of their offspring. Oyo Yakuri 1974;8:229–36. As cited by Shepard TH. Catalog of Teratogenic Agents. 10th ed. Baltimore, MD: The Johns Hopkins University Press, 2001:186.
5.Hogg MIJ, Golding RH, Rosen M. The effect of doxapram on fetal breathing in the sheep. Br J Obstet Gynaecol 1977;84:48–50.
6.Bairam A, Branchaud C, Beharry K, Rex J, Laudignon N, Papageorgiou A, Aranda JV. Doxapram metabolism in human fetal hepatic organ culture. Clin Pharmacol Ther 1991;50:32–8.
7.Gupta PK, Moore J. The use of doxapram in the newborn. J Obstet Gynaecol Br Commonw 1973;80:1002–6.