Fetal Risk Summary
Doxepin is a tricyclic antidepressant. It was not teratogenic in rats, rabbits, monkeys, and dogs (1,2 and 3). At the highest doses used, however, an increase in neonatal death was observed in rats and rabbits (1,2).
No published reports linking the use of doxepin with human congenital malformations have been located (see also Imipramine). Because of the relatively low molecular weight (316 for the hydrochloride salt), placental transfer of the drug to the fetus should be expected.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 118 newborns had been exposed to doxepin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 12 (10.2%) major birth defects were observed (4.5 expected), including (observed/expected) cardiovascular defects (2/1), oral clefts (2/0.2), and polydactyly (2/0.3). No anomalies were observed in three other categories of malformations (spina bifida, limb reduction defects, and hypospadias) for which specific data were available. The total number of major birth defects and the cases of polydactyly are suggestive of an association, but other factors, including concurrent drug use and chance, may be involved.
Paralytic ileus has been observed in an infant exposed to doxepin at term (4). The condition was thought to be due primarily to chlorpromazine, but the authors speculated that the anticholinergic effects of doxepin worked synergistically with the phenothiazine.
Breast Feeding Summary
Doxepin and its active metabolite, N-desmethyldoxepin, are excreted into breast milk (5,6 and 7). Three case histories describing the use of this agent during lactation have been published.
A 36-year-old woman was treated with doxepin, 10 mg daily, for approximately 5 weeks starting 2 weeks after the birth of her daughter (5). The dose was increased to 25 mg three times daily 4 days before the wholly breast-fed 8-week-old infant was found pale, limp, and near respiratory arrest. Although drowsiness and shallow respirations continued on admission to the hospital, the baby made a rapid recovery and was normal in 24 hours. A peak milk concentration of doxepin, 29 ng/mL, occurred 45 hours after a dose, while two levels obtained just prior to a dose (12 hours after the last dose in each case) were 7 and 10 ng/mL, respectively. Milk concentrations of the metabolite ranged from not detectable (lower limit of detection 7 ng/mL) to 11 ng/mL. The averages of nine determinations for doxepin and the metabolite in the milk were 18 and 9 ng/mL, respectively. Maternal serum doxepin and N-desmethyldoxepin levels ranged from trace to 21 ng/mL (average 15 ng/mL) and 3366 ng/mL (average 57 ng/mL), respectively. The milk:serum ratio for doxepin on two determinations was 0.9, while ratios for the metabolite were 0.12 and 0.17. Doxepin was almost undetectable (estimated to be 3 ng/mL) in the infant’s serum, but the levels of the metabolite on two occasions were 58 and 66 ng/mL, demonstrating marked accumulation in the infant’s serum. The initial infant urine sample contained 39 ng/mL of the metabolite.
The second case involved a 26-year-old woman, 30 days postpartum, who was treated with doxepin (150 mg every night) for a major depressive disorder (6). Blood samples were obtained a mean 18 hours after a dose on days 7, 14, 22, 28, 36, 43, 50, and 99 days of treatment. On the same days that blood specimens were drawn, milk samples were collected at the start of feeding (17.2 hours after the last dose) and at the end of feeding (17.7 hours after the last dose). Plasma concentrations of doxepin varied between 35 and 68 ng/mL, with a mean value of 46 ng/mL. Levels for the metabolite, N-desmethyldoxepin, ranged from 65 to 131 ng/mL, with a mean of 90 ng/mL. Mean pre- and post-feed milk:plasma ratios for doxepin were 1.08 (range 0.511.44) and 1.66 (range 0.792.39), respectively, and for the metabolite, 1.02 (range 0.541.45) and 1.53 (range 0.852.35), respectively. A plasma sample drawn from the infant on day 43 showed no detectable doxepin (sensitivity 5 ng/mL) and 15 ng/mL of the metabolite. No adverse effects of the exposure to doxepin were observed in the infant.
Muscle hypotonia, drowsiness, poor sucking and swallowing, and vomiting were reported in a 9-day-old breast-fed, 2950-g male baby whose mother was taking doxepin 35 mg/day (7). The mother had been started on doxepin during the 3rd trimester of pregnancy and continued the antidepressant postpartum. The normal, full-term, 3030-g infant had Apgar scores of 10 and 10 at 1 and 5 minutes, respectively. Breast feeding began 8 hours after birth. Hyperbilirubinemia (indirect bilirubin 17 mg/dL) was diagnosed at age 3 days and treated with blue-light phototherapy. He was discharged at age 5 days with a bilirubin of 9 mg/dL and a weight of 3100 g. At presentation 9 days after birth, jaundice was again present (indirect bilirubin 18 mg/dL) and was treated with 24 hours of phototherapy. The concentrations of doxepin and metabolite in the infant’s serum at 11 days of age, 2 hours after breast feeding, were about 10 ng/mL and
Adverse effects were observed in two of the three cases cited above and were potentially lethal to one infant. Based on these reports, doxepin should be avoided during lactation. The American Academy of Pediatrics classifies doxepin as an agent whose effect on the nursing infant is unknown but may be of concern (8).
- Owaki Y, Momiyama H, Onodera N. Effects of doxepin hydrochloride administered to pregnant rats upon the fetuses and their postnatal development. Oyo Yakuri 1971;5:91324. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:243.
- Owaki Y, Momiyama H, Onodera N. Effects of doxepin hydrochloride administered to pregnant rabbits upon the fetuses. Oyo Yakuri 1971;5:90512. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:243.
- Product information. Sinequan. Pfizer, 2000.
- Falterman CG, Richardson CJ. Small left colon syndrome associated with maternal ingestion of psychotropic drugs. J Pediatr 1980;97:30810.
- Matheson I, Pande H, Alertsen AR. Respiratory depression caused by N-desmethyldoxepin in breast milk. Lancet 1985;2:1124.
- Kemp J, Ilett KF, Booth J, Hackett LP. Excretion of doxepin and N-desmethyldoxepin in human milk. Br J Clin Pharmacol 1985;20:4979.
- Frey OR, Scheidt P, von Brenndorff AI. Adverse effects in a newborn infant breast-fed by a mother treated with doxepin. Ann Pharmacother 1999;33:6903.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.