bupropion

BUPROPION

Fetal Risk Summary

Bupropion is a unique antidepressant of the aminoketone class that differs from other antidepressants in that it does not inhibit monoamine oxidase and does not alter the reuptake of norepinephrine or serotonin (1). Anticholinergic effects are much less frequent and less severe than those observed with other antidepressants (1). No published reports on the use of bupropion in human pregnancy have been located, but data from a surveillance study and a pregnancy registry are presented below.

Reproduction studies in rats and rabbits at doses up to 15 to 45 times the human dose revealed no definitive evidence of impaired fertility or fetal harm (2). A slight increase in nonspecific fetal abnormalities, however, was observed in two studies with rabbits (2).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, three newborns had been exposed to bupropion during the 1st trimester (F. Rosa, personal communication, FDA, 1993). No major birth defects were observed (none expected).

A manufacturer's pregnancy registry reported 14 pregnancy exposures that had occurred before the establishment of the reg istry (3). In three of the cases, bupropion was discontinued before conception, and one case was lost to follow-up. Details on the timing of the exposures for the remaining 10 cases were incomplete. The outcomes were two spontaneous abortions (SABs) and eight live infants without birth defects. Over a 3-year period (September 1997 to August 2000), the registry enrolled 236 pregnancies exposed to bupropion that had been reported prospectively (before the pregnancy outcome was known). Of these, the outcomes of 97 pregnancies were pending and 51 had been lost to follow-up. The remaining 88 pregnancies involved 90 outcomes (2 sets of twins). Exposures occurred in the 1st trimester in 65 pregnancies (66 infants; 1 set of twins), in the 2nd trimester in 18 (19 infants; 1 set of twins), and in the 3rd trimester in 5 (5 infants). Among 1st trimester exposed cases, there were 7 SABs, 1 elective abortion, 1 infant with bilateral clubfeet, and 57 live births without reported birth defects. All of the 2nd and 3rd trimester exposures ended with live births with no reported defects. Although only one birth defect was reported, the possibility of additional birth defects being reported could not be excluded (3). (See required statement below.) There were eight outcomes with birth defects reported retrospectively (after the pregnancy outcome was known) (3). Although retrospective reports are often biased toward reporting adverse outcomes, and not normal infants, the defects described were: one kidney, a bicornuate uterus, and double vagina with one opening to outside; unspecified cardiac defects and omphalocele; hypoplastic right heart, atrial septal defect, ventricular septal defect, pulmonary atresia, left transposition of the great vessels, and transverse heart; SAB at 15 weeks' with unspecified congenital heart defect; hypoplastic left heart, diaphragmatic hernia, cleft lip and palate, absence of left radius, hemivertebrae, ear tags, microcephaly, and intrauterine growth retardation; gastroschisis; induced abortion at 19 weeks' due to transverse limb deficiencies, humero radioulnar, intercalary transverse meromelias bilateral, tibiofibular intercalary transverse meromelia of the lower limbs, missing digits of hands bilateral, oligodactyly, imperforate anus, cleft palate, short neck, and intraabdominal calcifications on ultrasound, normal chromosomes, no autopsy; stillborn at 38 weeks', hydrocephalus on visual examination, no autopsy.

Required statement: Committee consensus. After reviewing the 90 prospectively reported pregnancy outcomes, the Bupropion Pregnancy Registry Advisory Committee concludes that this sample is of insufficient size to reliably compute a birth defect risk, and no conclusions can be made regarding the possible teratogenic risk of bupropion. This sample size does not allow for a formal comparison of the frequency of birth defects.

Breast Feeding Summary

Bupropion is excreted into human breast milk. A 37-year-old lactating woman was treated with the drug, 100 mg, three times daily (4). She was nursing her 14-month-old infant twice daily at times corresponding to 9.5 and 7.5 hours after a dose. Peak milk concentrations of bupropion occurred 2 hours after a 100-mg dose with a value of 0.189 µg/mL, but the peak plasma level measured, 0.072 µg/mL, occurred at 1 hour. The milk:plasma ratios at 0, 1, 2, 4, and 6 hours after a dose were 7.37, 2.49, 4.31, 8.72, and 6.24, respectively. Two metabolites, hydroxybupropion and threohydrobupropion, were also measured with peak concentrations of both occurring at 2 hours in milk and plasma. The ranges of milk levels and milk:plasma ratios for the metabolites were 0.093–0.132 µg/mL and 0.366–0.443 µg/mL, respectively, and 0.09–0.11 and 1.23–1.57, respectively. The levels of a third metabolite, erythrohydrobupropion, were too low to be measured in breast milk (test sensitivity 0.02 µg/mL). No adverse effects were observed in the infant nor was any drug or metabolite found in his plasma, an indication that accumulation had not occurred. However, the American Academy of Pediatrics considers antidepressants a class of drugs whose effect on the nursing infant is unknown but may be of concern (5).

References

1. Weintraub M, Evan P. Bupropion: a chemically and pharmacologically unique antidepressant. Hosp Form 1989;24:254–9.
2. Product information. Wellbutrin. Burroughs Wellcome Co., 1993.
3. The Glaxo Wellcome Bupropion Pregnancy Registry. Interim Report, 1 September 1997 through 31 August 2000. December 2000.
4. Briggs GG, Samson JH, Ambrose PJ, Schroeder DH. Excretion of bupropion in breast milk. Ann Pharmacother 1993;27:431–3.
5. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.
   
   

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