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.
The authors thank Lisa Yu for assay development. This work was
supported by funding from the Tobacco-Related Disease Research
18 Briggs GG, Samson JH, Ambrose PJ, et al. Excretion of bupropion in breast
Program (9IT-0192), and the US Public Health Service (DA 02277)
milk. Ann Pharmacother 1993;27:431–3.
from the National Institute on Drug Abuse. The study was carried out
19 Baab SW, Peindl KS, Piontek CM, et al. Serum bupropion levels in 2
at the General Clinical Research Center at San Francisco General
breastfeeding mother-infant pairs. J Clin Psychiatry 2002;63:910–1.
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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21 Jorenby DE, Leischow SJ, Nides MA, et al. A controlled trial of sustained-
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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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Candida glabrata: an emergent opportunist in vulvovaginitis Rafael Buitrón-García-Figueroa,* Javier Araiza-Santibáñez,** Erich Basurto-Kuba,*** and Alexandro Bonifaz-Trujillo** Abstract Background: Candida genus has various species. The incidence of C. glabrata has presented itself with more frequency over the past years with clinical importance. Methods: A case study was made
diisopropylphenol) is rare. We report a case of a 26-year-oldmale nurse in which autopsy showed unspecific signs of in-toxication. Criminological evidence pointed towards propofolabuse and/or overdose. Intravenously administered propofolis a fast as well as short acting narcotic agent. Therefore itseemed questionable whether the deceased was able to self-administer a lethal overdose before lo