Phenacetin

Name: PHENACETIN
Class: Analgesic/Antipyretic
Risk Factor: B

Fetal Risk Summary

Phenacetin, in combination products, is routinely used during pregnancy. It is metabolized mainly to acetaminophen (see also Acetaminophen).
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 5,546 of which had 1st trimester exposure to phenacetin (1, pp. 286–295). Although no evidence was found to suggest a relationship to large categories of major or minor malformations, possible associations were found with several individual defects (1, p. 471): Craniosynostosis (6 cases) Adrenal syndromes (5 cases) Anal atresia (7 cases) Accessory spleen (5 cases) The statistical significance of these associations is unknown and independent confirmation is required. Further, phenacetin is rarely used alone, being consumed usually in combination with aspirin and caffeine. For use anytime during pregnancy, 13,031 exposures were recorded (1, p. 434). With the same qualifications, possible associations with individual defects were found (1, p. 483): Musculoskeletal (6 cases) Hydronephrosis (8 cases) Adrenal anomalies (8 cases) In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 368 newborns had been exposed to phenacetin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 24 (6.5%) major birth defects were observed (16 expected), including (observed/expected) 6/4 cardiovascular defects, 1/1 polydactyly, and 2/1 hypospadias. No anomalies were observed in three other defect categories (oral clefts, spina bifida, and limb reduction defects) for which specific data were available. These data do not support an association between the drug and congenital defects.

Breast Feeding Summary

Phenacetin is excreted into breast milk, appearing along with its major metabolite, acetaminophen (2). A patient who consumed two tablets of Empirin Compound with Codeine No. 3 (aspirin-phenacetin-caffeine-codeine) produced an average phenacetin milk concentration of 71 ng/mL (2). Milk:plasma ratios in this and a second patient varied from 0.16 to 0.90 (2).

References

1. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
2. Findlay JWA, DeAngelis RL, Kearney MF, Welch RM, Findlay JM. Analgesic drugs in breast milk and plasma. Clin Pharmacol Ther 1981;29:625–33.

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