Amitriptyline Risk Summary

Risk Factor: CM
Class: Central nervous system drugs / Antidepressants

Fetal Risk Summary

Two reviews found reports of amitriptyline-induced teratogenicity in animals: encephaloceles and bent tails in hamsters (1) and skeletal malformations in rats (2). However, reproduction studies conducted by the manufacturer in mice, rats, or rabbits with oral doses of 2 to 40 mg/kg/day (up to 13 times the maximum recommended human dose [MRHD]) revealed no evidence of teratogenicity (3). The manufacturer does cite the teratogenicity of amitriptyline in mice, hamsters, rats, and rabbits when higher doses were used (3).

The manufacturer states that amitriptyline crosses the placenta (3). The relatively low molecular weight (about 314) is consistent with this finding.

In humans, limb reduction anomalies have been reported with amitriptyline (4,5). However, analysis of 522,630 births, 86 with 1st trimester exposure to amitriptyline, did not confirm an association with this defect (6,7,8,9,10,11,12 and 13). Reported malformations other than limb reduction defects after therapeutic dosing include the following (8,12,13 and 14): Micrognathia, anomalous right mandible, left pes equinovarus (1 case) Swelling of hands and feet (1 case) Hypospadias (1 case) Bilateral anophthalmia (1 case) A case of maternal suicide attempt with a combination of amitriptyline (725 mg) and perphenazine (58 mg) at 8 days' gestation was described in a 1980 abstract (15). An infant was eventually delivered with multiple congenital defects. The abnormalities included microcephaly, cotton-like hair with pronounced shedding, cleft palate, micrognathia, ambiguous genitalia, foot deformities, and undetectable dermal ridges (15).

Thanatophoric dwarfism was found in a stillborn infant exposed throughout gestation to amitriptyline (>150 mg/day), phenytoin (200 mg/day), and phenobarbital (300 mg/day) (16). The cause of the malformation could not be determined, but both drug and genetic etiologies were considered.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 467 newborns had been exposed to amitriptyline during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 25 (5.4%) major birth defects were observed (20 expected). Specific data were available for six defect categories, including (observed/expected) 6/5 cardiovascular defects, 0/1 oral clefts, 0/0 spina bifida, 2/1 polydactyly, 2/1 limb reduction defects, and 1/1 hypospadias. These data do not support an association between the drug and the defects.

Neonatal withdrawal after in utero exposure to other antidepressants (see Imipramine), but not with amitriptyline, has been reported. However, the potential for this complication exists because of the close similarity among these compounds. Urinary retention in the neonate has been associated with maternal use of nortriptyline, an amitriptyline metabolite (see Nortriptyline) (17).

In summary, although occasional reports have associated the therapeutic use of amitriptyline with congenital malformations, the bulk of the evidence indicates these widely used drugs are relatively safe during pregnancy. The single case of gross overdose is suggestive of an association between amitriptyline, perphenazine, or both, and malformations, but without confirming evidence no conclusions can be determined. Because of the experience with tricyclic antidepressants, one review recommended they were preferred during gestation over other antidepressants (2).

Breast Feeding Summary

Amitriptyline and its active metabolite, nortriptyline, are excreted into breast milk (18,19 and 20). A recent study has measured the amount of a second active metabolite, E-10-hydroxynortriptyline, in milk (21).

Serum and milk concentrations of amitriptyline in one patient were 0.14 and 0.15 g/mL, respectively, a milk:plasma ratio of 1.0 (18). No drug was detected in the infants serum. In another patient, it was estimated that the baby received about 1% of the mother's dose (20). No clinical signs of drug activity were observed in the infant.

In the third study, the mother was treated with 175 mg/day of amitriptyline (21). Milk and maternal serum samples were analyzed for active drug and active metabolites on postpartum days 126. Amitriptyline serum levels ranged from 24 ng/mL (day 1) to 71 ng/mL (days 326), while those in the milk ranged from 24 ng/mL (day 1) to only 54% of the serum levels on days 226. Nortriptyline serum levels ranged from 17 ng/mL (day 1) to 87 ng/mL (day 26) with milk levels 74% of those in the serum. Mean concentration of the second metabolite, E-10-hydroxynortriptyline, was 127 ng/mL (days 126) in the serum and 70% of that in the milk. The total dose (parent drug plus metabolites) consumed by the male infant on day 26 was estimated to be 35 g/kg (80 times lower than the mother's dose) (21). None of the compounds were detected in the nursing infant's serum on day 26 and no adverse effects, including sedation, were observed in him.

Although levels of amitriptyline and its metabolite have not been detected in infant serum, the effects of exposure to small amounts in the milk are not known (18,19 and 20,22). The American Academy of Pediatrics classifies amitriptyline as a drug whose effect on the nursing infant is unknown but may be of concern (23).

References

1. Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD:Johns Hopkins University Press, 1989:445.
2. Elia J, Katz IR, Simpson GM. Teratogenicity of psychotherapeutic medications. Psychopharmacol Bull 1987;23:53186.
3. Product information. Elavil. AstraZeneca, 2000.
4. McBride WG. Limb deformities associated with iminodibenzyl hydrochloride. Med J Aust 1972;1:492.
5. Freeman R. Limb deformities: possible association with drugs. Med J Aust 1972;1:606.
6. Australian Drug Evaluation Committee. Tricyclic antidepressants and limb reduction deformities. Med J Aust 1973;1:7689.
7. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977:3367.
8. Idanpaan-Heikkila J, Saxen L. Possible teratogenicity of imipramine/chloropyramine. Lancet 1973;2:2823.
9. Rachelefsky GS, Glynt JW, Ebbin AJ, Wilson MG. Possible teratogenicity of tricyclic antidepressants. Lancet 1972;1:838.
10. Banister P, Dafoe C, Smith ESO, Miller J. Possible teratogenicity of tricyclic antidepressants. Lancet 1972;1:8389.
11. Scanlon FJ. Use of antidepressant drugs during the first trimester. Med J Aust 1969;2:1077.
12. Crombie DL, Pinsent R, Fleming D. Imipramine in pregnancy. Br Med J 1972;1:745.
13. Kuenssberg EV, Knox JDE. Imipramine in pregnancy. Br Med J 1972;2:292.
14. Golden SM, Perman KI. Bilateral clinical anophthalmia: drugs as potential factors. South Med J 1980;73:14047.
15. Wertelecki W, Purvis-Smith SG, Blackburn WR. Amitriptyline/perphenazine maternal overdose and birth defects (abstract). Teratology 1980;21:74A.
16. Rafla NM, Meehan FP. Thanatophoric dwarfism: drugs and antenatal diagnosis. A case report. Eur J Obstet Gynecol Reprod Biol 1990;38:1615.
17. Shearer WT, Schreiner RL, Marshall RE. Urinary retention in a neonate secondary to maternal ingestion of nortriptyline. J Pediatr 1972;81:5702.
18. Bader TF, Newman K. Amitriptyline in human breast milk and the nursing infants serum. Am J Psychiatry 1980;137;8556.
19. Wilson JT, Brown D, Cherek DR, Dailey JW, Hilman B, Jobe PC, Manno BR, Manno JE, Redetzki HM, Stewart JJ. Drug excretion in human breast milk. Principles, pharmacokinetics and projected consequences. Clin Pharmacokinet 1980;5:166.
20. Brixen-Rasmussen L, Halgrener J, Jorgensen A. Amitriptyline and nortriptyline excretion in human breast milk. Psychopharmacology (Berlin) 1982;76:945.
21. Breyer-Pfaff U, Nill K, Entenmann A, Gaertner HJ. Secretion of amitriptyline and metabolites into breast milk. Am J Psychiatry 1995;152:8123.
22. Erickson SH, Smith GH, Heidrich F. Tricyclics and breast feeding. Am J Psychiatry 1979;136:1483.
23. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.

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