DICHLORALPHENAZONE

Fetal Risk Summary

Dichloralphenazone is a sedative hypnotic composed of two molecules of chloral hydrate (a sedative/hypnotic) (see also Chloral Hydrate) bound together with the analgesic/antipyretic, phenazone (see also Antipyrine) (1). Antipyrine and chloral hydrate are derived from dichloralphenazone and the latter drug is metabolized to the active agent, trichloroethanol. Little information is available on the reproductive effects of antipyrine, chloral hydrate, or the prodrug, dichloralphenazone, a component, along with isometheptene and acetaminophen, of several proprietary mixtures commonly used for tension and vascular (migraine) headaches (see also Isometheptene and Acetaminophen).

Two studies have been located that examined the effect of dichloralphenazone in pregnant rats (1,2). No teratogenic or other adverse fetal effects were observed when doses ranging from 50 to 500 mg/kg/day were fed to rats throughout gestation.

No published reports describing the use of dichloralphenazone in human pregnancy have been located, although one Reference commented that the drug has been “widely used” during pregnancy (3). The Collaborative Perinatal Project recorded 71 1st trimester exposures to chloral hydrate (4, pp. 336–44), one of the drugs derived from dichloralphenazone. From this group, eight infants with congenital defects were observed (standardized relative risk [SRR] 1.68). When only malformations with uniform rates by hospital were examined, the SRR was 2.19. Neither of these relative risks reached statistical significance. Moreover, when chloral hydrate was combined with all tranquilizers and nonbarbiturate sedatives, no association with congenital malformations was found (SRR 1.13; 95% confidence interval [CI] 0.88–1.44). For use anytime during pregnancy, 358 exposures to chloral hydrate were discovered (4, p. 438). The nine infants with anomalies yielded a SRR of 0.98 (95% CI 0.45–1.84). (See also Antipyrine for additional information.)

Breast Feeding Summary

Dichloralphenazone is a prodrug composed of the sedative/hypnotic, chloral hydrate, bound together with the analgesic/antipyretic, phenazone. Trichlorethanol, an active metabolite of chloral hydrate, is excreted into human breast milk, as is phenazone (see Antipyrine).

Mild morning drowsiness was observed in a nursing infant of a woman taking 1300 mg (13 times the dose per capsule in the proprietary headache products mentioned above) of dichloralphenazone at bedtime (5). The mother was also taking chlorpromazine, 100 mg 3 times daily. Milk concentrations of trichloroethanol were 60% to 80% of the maternal serum levels. The metabolite was not detected in the infant's plasma 20 hours after a dose. Infant growth and development remained normal during the exposure and at follow-up 3 months after the drug was stopped. Apparently, no attempt was made in this study to determine the milk concentration of phenazone, the other component of dichloralphenazone.

References

1. McColl JD, Globus M, Robinson S. Effect of some therapeutic agents on the developing rat fetus. Toxicol Appl Pharmacol 1965;7:409–17. As cited in Shepard TH. Catalog of Teratogenic Agents. 7th ed. Baltimore, MD:Johns Hopkins University Press, 1992:131.
2. Onnis A, Grella P. The Biochemical Effects of Drugs in Pregnancy. Volume 1. West Sussex, England:Ellis Horwood Limited, 1984:60.
3. Lewis PJ, Friedman LA. Prophylaxis of neonatal jaundice with maternal antipyrine treatment. Lancet 1979;1:300–2.
4. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
5. Lacey JH. Dichloralphenazone and breast milk. Br Med J 1971;4:684.