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Bupropion in breast milk: an exposure assessment for potential treatment to prevent post-partum tobacco useJ S Haas, C P Kaplan, D Barenboim, P Jacob 3rd, N L Benowitz. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Objectives: To assess potential infant exposure to bupropion and its active metabolites in breast milk suchas would occur during treatment to prevent post-partum relapse to tobacco use, and to compare theconcentrations of bupropion in urine and saliva with plasma and breast milk.
Design and setting: Cohort study, outpatient clinical research centre.
Subjects: Ten healthy post-partum volunteers who agreed to take bupropion for seven days, pump anddiscard their breast milk, and have samples of breast milk, plasma, saliva, and urine analysed.
Intervention: Bupropion 150 mg a day for three days and then 300 mg a day for four days.
Main outcome measures: Concentrations of bupropion and its active metabolites (hydroxybupropion,erythrohydrobupropion, threohydrobupropion) in breast milk, plasma, saliva, and urine. Determination ofaverage infant exposure.
Results: The calculated average dosage of bupropion in breast milk was 6.75 mg/kg/day. Therefore, theaverage infant exposure is 0.14 % of the standard adult dose of bupropion, corrected for the difference inbody weight. Considering the sum of bupropion and its active metabolites, the average infant exposure is expected to be 2% of the standard maternal dose on a molar basis. The concentration of bupropion and its active metabolites in breast milk was not associated with age, body mass index, use of oral contraceptive . . . . . . . . . . . . . . . . . . . . . . .
pills, age of infant, or the frequency of breast feeding at the time the study was initiated. The coefficient of determination (r2) between the concentration of bupropion in breast milk and in urine was 0.77 Conclusions: Bupropion and its active metabolites are present in the breast milk of lactating women. The concentrations of bupropion in breast milk and urine were highly correlated. These results indicate that the daily dose of bupropion and metabolites that would be delivered to an infant of a woman taking a therapeutic dose of bupropion is small. These results suggest that the effectiveness of bupropion to prevent post-partum relapse to tobacco use should be evaluated without excluding women who plan to breast . . . . . . . . . . . . . . . . . . . . . . .
Cigarette smoking is the leading cause of preventable Bupropion is an effective therapy for smoking cessation morbidity and mortality for women in the USA.1 One and relapse prevention; it is as effective or more effective estimate suggests that 13% of all deaths among women than nicotine replacement products.20–23 Bupropion is an are a direct result of tobacco use, and that smoking shortens a atypical antidepressant that has both dopaminergic and woman’s life by an average of 15 years.2 Although tobacco noradrenergic activity.24 Bupropion is categorised for use in use has been decreasing among women, a recent national pregnancy by the US Food and Drug Administration as report indicates that 24% of women still report current category B (that is, animal studies show no risk, or animal smoking.3 Pregnancy is a pivotal event of young adult- studies with minimal risk with no risk shown in humans). A hood for many women. Women are much more likely to slow release formulation became available in 1998, and this quit smoking around the time of pregnancy than at any formulation is marketed for the treatment of smoking other.4 While the prevalence of smoking has also decreased cessation. There are several reasons why bupropion may be among pregnant women, 12% of pregnant women report particularly useful to prevent post-partum relapse, including current smoking.3 Unfortunately, women who quit during mood stabilisation, decreased fatigue, decreased tobacco pregnancy have extremely high rates of relapse during the craving, and weight loss.20–22 To date, there is no literature months immediately following delivery.5–9 Behavioural inter- examining the use of bupropion or other antidepressants as ventions during pregnancy and the post-partum period have part of an intervention to prevent post-partum relapse to not been associated with an increase in post-partum tobacco tobacco use. Bupropion, like other psychotropic medications, is lipid soluble and therefore secreted into breast milk.
Medications are typically avoided in lactating women Information about the use of bupropion by lactating women is limited. Case reports note non-detectable plasma concen- Approximately 65% of women breast feed in the early post- trations of bupropion and its metabolites in three infants of partum period,12 although the prevalence of breast feeding among women who quit smoking during pregnancy is This study was designed to measure the amount of probably lower than the general population.13 Few studies bupropion and its active metabolites in the breast milk of have quantified the exposure of infants to medications women who are lactating but not breast feeding to ascertain consumed by their breast feeding mothers.14–19 This practice whether this drug might be given safely to post-partum leads women and their physicians to avoid medications, women, who are or may be breast feeding, to prevent post- perhaps unnecessarily, or encourages women not to breast partum relapse to tobacco use. We also examined concentra- tions of bupropion in urine and saliva compared to plasma and breast milk. If highly correlated, saliva or urine calculating the time elapsed between the start of the clinic measurement would allow for less invasive monitoring of visit and the scheduled time of the last pill ingestion.
lactating women taking bupropion in the post partum period.
Measurement of bupropion and its active metabolites, hydroxybupropion, erythrohydrobupropion, and threohydro- Ten healthy, paid volunteers were recruited through adver- bupropion were quantitated in breast milk, plasma, saliva tisements posted in clinic waiting rooms, and advertisements and urine using liquid chromatography-tandem mass spec- in parent periodicals. Women over the age of 18 years were trometry (LC-MS/MS). The method is similar to the one eligible to participate if they were currently breast feeding at reported by Hsyu et al, but is capable of measuring the least three times per day and planned to discontinue breast erythrohydrobupropion and threohydrobupropion individu- feeding in the next few weeks. We excluded women who: (1) ally.25 Deuterium labelled internal standards, which were were currently using any psychoactive medications; (2) had synthesised in our laboratory, were used as internal current major depression, schizophrenia, or bipolar disorder; standards. The lower limit of quantitation of the bupropion and (3) had a history of a seizure disorder, anorexia or assay (LLOQ) is 1 ng/ ml. Samples were frozen and assayed bulimia, or intolerance to bupropion.
in one batch at the completion of the study. There was nosignificant change in the concentration of bupropion and metabolites stored for one month in a freezer at 220˚C.
Subjects were studied as outpatients at the clinical study Quality control procedures that are appropriate for pharmaco- centre at San Francisco General Hospital. An eligible woman was scheduled for an initial study visit at the time that sheintended to stop breast feeding. At this visit eligibility was confirmed, informed consent was obtained, a health history An average daily dose of bupropion and each of its active was performed and blood pressure, weight and height were metabolites in breast milk was calculated. An average infant measured. At this visit, women were also instructed on the milk consumption of 0.15 l/kg/day was assumed.26 Since use of a breast pump, and provided with one if they did not bupropion metabolites are pharmacologically active,24 the already have one available. Women were instructed to stop exposure of the infant to the sum of bupropion and its breast feeding on that day and to begin pumping, and metabolites was estimated, and compared (on a molar basis) discarding, their breast milk at least three times per day. The to the typical maternal weight2normalised exposure to following day, women were instructed to initiate bupropion bupropion. The Pearson correlation coefficients (r) was used SR 150 mg orally once a day. Women were instructed to to calculate a coefficient of determination (r2) to compare the increase the dosage to 300 mg a day after three days. Phone plasma, saliva, and urine concentrations of bupropion with contact was maintained with women during this period to breast milk concentration to determine whether saliva or facilitate compliance. On the seventh day of the protocol, urine measurement could be used (instead of plasma) to women came in for a second study visit. At this visit, a single monitor bupropion concentrations in breast milk.
sample of plasma, saliva, urine, and breast milk were eachobtained. The initial 3 ml of breast milk was obtained with the use of electric breast pump. Pill bottles were collected to The median age of the 10 women who participated in this ensure compliance with the medication dosing. We calcu- protocol was 29 years (range 22–37 years). Their median lated an approximate time since the last dose ingestion by weight was 59.4 kg (range 54.1–95.5) and their median body Table 1 Concentrations of bupropion and active metabolites in breast milk, plasma,urine, and saliva Mean (SD) erythrohydrobupropion 72.1(38.3) Table 2 Infant dose of bupropion and metabolites *Molecular weights: bupropion 240; hydroxybupropion 256; erythrohydrobupropion and threohydrobupropion 242.
ÀInfant dose based on breast milk concentration and infant consumption of 0.15 l/kg/day.
`Maternal bupropion dose based on 300 mg/day = 5 mg/kg/day = 20833 nM/kg/day.
Metabolite percentages based on bupropion molar equivalents.
mass index was 25.3 kg/m2 (range 20.9–38.4). At the timeof participation, the average age of the infants of these women was 12.5 months. Half of the women were takingan oral contraceptive pill. No other medications were being Although women are much more likely to quit smoking used by any of the participants. The median number of hours around the time of pregnancy than at any other time, women since the last dose of bupropion was 2.5 hours (range 1–12 who quit during pregnancy have extremely high rates of hours). The concentrations of bupropion and its active relapse during the months immediately following delivery.
metabolites in breast milk, plasma, urine, and saliva are While bupropion has been shown to be effective in smoking shown in table 1. The average (SD) breast milk to plasma cessation and delaying relapse, it has not been evaluated as (M/P) bupropion ratio was 2.8 (3.7). The average M/P ratios a treatment to prevent post-partum relapse because of of hydroxybupropion, erythrohydrobupropion, and threo- concerns over potential exposure by an infant who is breast hydrobupropion were 0.1 (0.03), 0.9 (0.3), and 1.2 (0.3), fed. This study examines the potential exposure of an infant respectively. Since on average an infant drinks 0.15 l/kg/ breast fed by a woman taking bupropion, and determined day,26 the calculated dosage of bupropion in breast milk is that infant exposure to bupropion and its active metabolites 6.75 mg/kg/day (table 2). The estimated daily infant dosages in breast milk is low. These results are important for of the metabolites were: hydroxybupropion 15.75 mg/kg/day, designing clinical trials to prevent post-partum relapse that erythrohydrobupropion 10.80 mg/kg/day, and threohydrobu- The concentration of bupropion and its active metabo- lites in breast milk was not associated with age, body mass Therefore our estimates of exposure to bupropion are likely to index, age of infant, use of oral contraceptive pills, or the be high; the actual exposure to bupropion would be even less frequency of breast feeding at the time the study was than what we have estimated. Since the metabolites have longer half lives than bupropion and are generated slowly The coefficient of determination between the concentration from bupropion, these concentrations are expected to be at or of bupropion in breast milk and in urine was 0.77 (p , 0.01) near steady state. Thus, the estimates of exposure to (table 3). There was no significant association between saliva metabolites based on a single sample should be representa- or plasma bupropion concentrations and the concentration of bupropion in breast milk, although there were significant The women who participated had been breast feeding for correlations between plasma and saliva bupropion. No side an average of 12.5 months. It is possible that the milk effects were noted by any of the mothers.
composition after this length of breast feeding may bedifferent than that in the immediate post-partum period.
Although our results suggest that bupropion taken by a Bupropion and its active metabolites are present in the breast breast feeding mother should not present a concern for most milk of lactating women. These results indicate that the daily infants, exposure may be greater for some infants—for dose of bupropion and metabolites that would be delivered to an infant of a woman taking a therapeutic dose of bupropion Medications are typically avoided in lactating women is small. The estimated dose of bupropion taken up by the because of the potential exposure of their infants. Few infant milk was less than 0.2 % of the weight normalised studies have quantified the true exposure of infants to dose of an adult woman. The major metabolites of bupropion medications consumed by their breast feeding mothers.14–17 are active, producing equal or weaker inhibition of neuro- This practice leads women and their physicians to avoid transmitter uptake compared to bupropion.24 Since the medications, perhaps unnecessarily, or encourages women metabolites of bupropion have pharmacologic activity, the exposures of the metabolites should be considered as part of Pregnant women have been extensively targeted for the infant drug exposure as well. If one conservatively interventions to reduce prenatal tobacco use, primarily to assumes equimolar pharmacologic potency of the hydroxy- protect the health of their unborn child. These efforts have bupropion, erythrohydrobupropion, and threohydrobupro- been successful. Women are three times more likely to quit pion metabolites to the parent bupropion, and assumes smoking during their first pregnancy and the year preceding complete oral bioavailability in the infant, the total exposure this pregnancy than at any other time.4 Estimates suggest to bupropion and metabolites would be 2% of the weight that approximately 30–50% of women who smoke spon- normalised maternal bupropion dose. This dose in the infant is lower than 10% of maternal dose that has been used as a pregnancy.5 28 29 Prenatal educational and behavioural inter- guideline for drug safety during breast feeding.26 The failure ventions have been shown to increase cessation rates during to detect bupropion in three other breast fed infants whose pregnancy up to 50%.29–32 However, despite a high likelihood mothers were taking bupropion in doses of 150–300 mg daily of quitting around the time of pregnancy, many women doses supports the idea that infants are exposed to a very low relapse following delivery. Several studies have demonstrated high rates of smoking relapse post-partum, ranging from 40– The coefficients of determination for breast milk with 90% within six months.5–8 28 Bupropion has been shown to urine, saliva, and plasma concentrations of bupropion and its delay relapse to smoking in non-pregnant adults.22 Bupropion active metabolites were not high (with the exception of is generally safe and well tolerated, with relatively rare breast milk and urine bupropion concentrations). This adverse effect.21 Our results suggest that bupropion taken by suggests that future studies should not rely on these other a breast feeding mother should not present a concern for body fluids as surrogate markers for breast milk.
most infants. Particularly given the lack of success of The concentration of bupropion and its metabolites were measured in breast milk and in other body fluids at one point relapse,11 33–37 the effectiveness of bupropion to prevent post- in time. Sampling at multiple times was not performed.
partum smoking relapse should be evaluated in clinical trials Although the half life of bupropion is relatively long, there is without excluding women who are or may be breast feeding.
an absorption peak after ingestion of the sustained release During such studies, however, it would be advisable to preparation, peaking at 1–4 hours.27 Most of our subjects had measure bupropion and metabolites in infants, to confirm blood and milk samples taken around the time of the peak.
that the exposure is as low as expected.
17 Stowe ZN, Hostetter AL, Owens MJ, et al. The pharmacokinetics of sertraline excretion into human breast milk: determinants of infant serum concentrations.
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Hospital Medical Center with support of the Division of Research 20 Hurt RD, Sachs DP, Glover ED, et al. A comparison of sustained-release Resources, National Institute of Health (RR-00083).
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24 Ascher JA, Cole JO, Colin JN, et al. Bupropion: a review of its mechanism of antidepressant activity. J Clin Psychiatry 1995;56:395–401.
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Bupropion in breast milk: an exposure
assessment for potential treatment to prevent
post-partum tobacco use

J S Haas, C P Kaplan, D Barenboim, et al.
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