Article

Transfer of the antidepressant mirtazapine into breast milk

School of Medicine and Pharmacology, University of Western Australia, Perth City, Western Australia, Australia
British Journal of Clinical Pharmacology (Impact Factor: 3.88). 04/2007; 63(3):322-7. DOI: 10.1111/j.1365-2125.2006.02773.x
Source: PubMed

ABSTRACT

To investigate the transfer of mirtazapine and desmethylmirtazapine into milk and to calculate dose to the infant via milk.
Plasma and milk samples were obtained from eight breast-feeding women who were taking a median dose of 38 mg mirtazapine per day. Milk/plasma ratio (M/P) and infant doses were estimated by standard methods. The infants were examined clinically and in four infants blood was taken for analysis.
Mean (95% confidence interval) relative infant doses for mirtazapine and desmethylmirtazapine (n = 8) were 1.5% (0.8, 2.2) and 0.4% (0.2, 0.6) respectively. The mean M/P (area under curve n = 4, single or paired samples n = 3) was 1.1 (0.7,1.5) for mirtazapine and 0.6 (0.5, 0.7) for desmethylmirtazapine. No adverse effects were seen. Mirtazapine was detected (1.5 microg l(-1)) in only one of four infants tested.
We suggest that mirtazapine use by lactating women is safe for the breast-fed infant. Nevertheless, each decision to breast feed should always be made on the basis of an individual risk/benefit analysis.

Full-text

Available from: Rolland Kohan, Oct 11, 2014
British Journal of Clinical Pharmacology
DOI:10.1111/j.1365-2125.2006.02773.x
Br J Clin Pharmacol
63
:3 322327 322 © 2006 The Authors
Journal compilation © 2006 Blackwell Publishing Ltd
Correspondence
Emeritus Professor K. F. Ilett,
Pharmacology and Anaesthesiology
Unit, M510, School of Medicine and
Pharmacology, University of Western
Australia, Crawley, 6009 Western
Australia.
Tel:
+
618 9346 2985
Fax:
+
618 9346 3469
E-mail:
ken.ilett@uwa.edu.au
Keywords
breast feeding, desmethylmirtazapine,
human milk, infant dose, infant well-
being, mirtazapine
Received
2 March 2006
Accepted
23 June 2006
Published
OnlineEarly
13 September 2006
What is already known about this subject
•There is presently only a single case report on mirtazapine
transfer into breast milk and its effects in the breast-fed
infant.
What this study adds
Most importantly, we have provided quantitative data on the
absolute and relative infant doses of mirtazapine and its
active metabolite.
•We have also documented a lack of overt adverse effects in
the breast-fed infants and low or absent plasma
concentrations of mirtazapine in a subset of these infants.
Hence we now know that breast-fed infants are unlikely to
be adversely affected when their mothers need to take
mirtazapine.
Aims
To investigate the transfer of mirtazapine and desmethylmirtazapine into milk and to
calculate dose to the infant via milk.
Methods
Plasma and milk samples were obtained from eight breast-feeding women who were
taking a median dose of 38 mg mirtazapine per day. Milk/plasma ratio (M/P) and
infant doses were estimated by standard methods. The infants were examined
clinically and in four infants blood was taken for analysis.
Results
Mean (95% confidence interval) relative infant doses for mirtazapine and desmeth-
ylmirtazapine (
n
=
8) were 1.5% (0.8, 2.2) and 0.4% (0.2, 0.6) respectively. The
mean M/P (area under curve
n
=
4, single or paired samples
n
=
3) was 1.1 (0.7,1.5)
for mirtazapine and 0.6 (0.5, 0.7) for desmethylmirtazapine. No adverse effects were
seen. Mirtazapine was detected (1.5
µ
g l
1
) in only one of four infants tested.
Conclusion
We suggest that mirtazapine use by lactating women is safe for the breast-fed infant.
Nevertheless, each decision to breast feed should always be made on the basis of
an individual risk/benefit analysis.
Transfer of the antidepressant mirtazapine into
breast milk
J. H. Kristensen, Kenneth F. Ilett,
1,2
Jonathan Rampono,
3
Rolland Kohan,
4
& L. Peter Hackett
2
Pharmacy Department, Women’s and Children’s Health Service, Subiaco,
1
Pharmacology and Anaesthesiology Unit, School of Medicine and
Pharmacology, University of Western Australia, Crawley,
2
Clinical Pharmacology & Toxicology Laboratory, PathWest Laboratory Medicine,
Nedlands,
3
Department of Psychological Medicine, and
4
Department of Neonatal Services, Women’s and Children’s Health Service, Subiaco,
Australia
Page 1
Transfer of the antidepressant mirtazapine into breast milk
Br J Clin Pharmacol
63
:3 323
Introduction
Because of the 10–15% prevalence of depression in the
postnatal period, antidepressants are one of the most
frequently used drugs in lactation [1]. Children of
depressed mothers may exhibit behavioural problems
and delayed language development [2–5]. In women
with moderate and severe depressive disorders, it is
accepted that drug treatment during pregnancy and in
the postnatal period has significant benefits for both
mother and infant. Mirtazapine is classified as a norad-
renergic and specific serotonergic antidepressant which
also has effects at histamine receptors [6]. Its efficacy is
similar to that of tricyclic and the selective serotonin
reuptake inhibitor antidepressants [7]. It can be used as
first-line treatment [8] and, because of its action on
histamine, H
1
receptors may be preferred in some
patients with postnatal depression, when night-time
sedation is required. It is marketed as the racemate and
both enantiomers are presumed to contribute to the anti-
depressant activity [9, 10].
The only published information on the transfer of
mirtazapine into milk is a single case report [11]. In the
present study we have assessed infant dose via milk, and
the safety of breast feeding. Desmethylmirtazapine,
formed by CYP3A4, was also included because it has
steady-state plasma concentrations that are about 33%
of those of mirtazapine, and a similar but less active (5-
to 10-fold lower) pharmacological profile [10].
Materials and methods
Patients
Eight breast-feeding women who were being treated
with mirtazapine for perinatal and/or postnatal depres-
sion were recruited and gave written informed consent.
Study protocol and data collection
The study protocol was approved by the Ethics Com-
mittee of the Women’s and Children’s Health Service,
Subiaco, Australia. The women were studied at steady
state. Milk samples (6 ml by hand expression or electric
pump) were collected each time the infant was fed (3–
4 hourly) and unless otherwise specified were an equal
mixture of fore- and hind-milk. In four of the studies,
several paired fore- and hind-milk samples were also
collected in the post-absorption phase to investigate the
effect of milk fat content on drug transfer. Creamatocrit
was measured as previously described [12]. Plasma
samples (5 ml heparinized) were also taken from seven
of the women, who agreed to blood sampling. Three
gave five to eight samples over the dose interval, while
the remainder gave only one or two samples. Infant
health and well-being were investigated by inquiry of
the mother and/or the referring physician and body
weight was assessed by reference to standard growth
charts [13]. The infants (except no. 3 who was unavail-
able) were also given a full clinical examination, includ-
ing a Denver development assessment [14]. A venous
blood sample (0.5–2 ml, heparinized) for drug assay
was also taken from four infants.
Materials
Authentic
rac-
mitrazapine and
rac-
desmethylmirtazap-
ine were obtained from Organon Australia Pty Ltd (Lane
Cove, Australia) and pethidine was from Mayne Pharma
Ltd (Melbourne, Australia). All other solvents and
chemicals were of analytical grade.
Analysis of
rac
-mirtazapine and
rac
-desmethylmir-
tazapine was by high-performance liquid chromatogra-
phy (HPLC). Pethidine (270 ng, internal standard) was
added to 1-ml aliquots of plasma, alkalinized with
0.1 ml
M
NaOH and extracted into 10 ml diethylether.
After centrifugation, the organic phase (9 ml) was back-
extracted into 0.2 ml 0.05
M
HCl and aliquots of the acid
phase injected onto the HPLC. Milk samples were
extracted similarly except that the ‘method of addition’
[15] was used. The HPLC system consisted of a RP
Select B column (250
×
4.6 mm; Merck KGaA, Darm-
stadt, Germany), a mobile phase of 20% v/v acetonitrile
in 45 m
M
NaH
2
PO
4
(pH 3) pumped at 1.5 ml min
1
and
detection at 210 nm. Retention times for desmethylmir-
tazapine, mirtazapine and pethidine were 6.2, 8 and
12.2 min, respectively. Both intra- and interday relative
standard deviations (RSD;
n
=
5) for mirtazapine
(25 and 350
µ
g l
1
) and desmethylmirtazapine (9 and
300
µ
g l
1
) in plasma were
<
5.4% and
<
3% and in milk
were
<
8.9% and
<
9.3%, respectively. The limit of detec-
tion for both analytes in milk and plasma was 1
µ
g l
1
for a 1-ml sample.
Data analysis
Where complete milk and plasma concentration–time
data over a dose interval were available (
n
=
3),
areas under the respective concentration–time curves
(AUC
0
24 h
) were calculated [16] and the milk to plasma
ratio (M/P
AUC
) was then calculated from these data [15].
The average drug concentration in milk or plasma was
calculated as
C
av
=
(AUC
0
24 h
)/
τ
, where
τ
=
the dose
interval. In patients where one or two plasma concen-
tration measurements were available (
n
=
4),
C
single/dual
in
plasma was taken as the single, or average of two mea-
surements made on the study day and M/P
single/dual
was
calculated relative to the respective milk
C
av.
Absolute
and relative infant doses were calculated as previously
described [17]. In graphing the milk concentration–time
Page 2
J. H. Kristensen et al.
324
63
:3
Br J Clin Pharmacol
data (Figure 1) and estimating AUC
milk,
the concentra-
tion values for paired fore- and hind-milk samples were
averaged and plotted/analysed against the average of
their sampling times. Data have been summarized as
mean [95% confidence interval (CI), or range] or
median (range, or 25th and 75th percentiles) and differ-
ences between means examined by Student’s
t
-test or a
paired
t
-test (SigmaStat Ver 3.1; SPSS Inc., Chicago, IL,
USA).
Results
The mothers had a mean age of 35 years (range 32–
36 years), a mean body weight of 77 kg (range 58–
97 kg) and all were taking a single daily dose of mir-
tazapine (median 38 mg; range 30–120 mg). Therapy
had commenced a median of 32 days (range 6–129 days)
prior to the study. Concomitant drug therapy was
oxazepam, inhaled fluticasone and salbutamol in patient
1, inhaled fluticasone and salbutamol in patient 4 and
escitalopram (20 mg kg
1
day
1
) in patient 6. The infants
were two females and six males with a mean age of
6.3 months (range 1.5–13 months) and a mean weight
of 7.4 kg (range 5.5–10.5 kg) on the study day. Five of
the infants had achieved weight for age within 25th to
75th percentiles and the remaining three were within the
10th and 25th percentiles at the time of study. Of the
three infants below the 25th percentile, one was small
for gestational age at birth and the other two had corre-
spondingly low birth weights. Nevertheless, the paedi-
atric assessment done on seven infants revealed no
adverse findings and the mean Denver developmental
age was 101% (95% CI 92, 110) of the actual age. No
adverse drug-related effects were reported for any infant.
Milk and plasma concentration–time profiles for the
Figure 1
Milk and plasma concentration–time profiles for
rac-
mirtazapine (
, milk,
, plasma) and
rac-
desmethylmirtazapine (
, milk,
, plasma) in patients 1
to 8. The symbol (
) in the graph for patient 2 indicates the plasma concentration of mirtazapine measured in her infant
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
40
80
120
160
200
240
280
#1 #2
#3 #4
0
20
40
60
80
100
120
061218 24
061218 24
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
20
40
60
80
061218 24
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
10
20
30
40
50
60
061218 24
(hrs)
(hrs)
(hrs)
(hrs)
Page 3
Transfer of the antidepressant mirtazapine into breast milk
Br J Clin Pharmacol
63
:3 325
eight women are shown in Figure 1. The mean (95% CI;
n
=
8) milk
C
av
for mirtazapine was 53
µ
g l
1
(42, 65),
while the mean plasma
C
av
(
n
=
3) or
C
single/dual point
(
n = 4)
was 47 µg l
1
(24, 70). For desmethylmirtazapine, the
milk C
av
was 13 µg l
1
(9, 17), while the mean plasma
C
av
or C
single/dual point
was 19 µg l
1
(11, 26). The mean
(n = 7) M/P values were 1.1 (0.7, 1.5) for mirtazapine
and 0.6 (0.5, 0.7) for desmethylmirtazapine.
Table 1 summarizes the maternal and infant doses and
drug concentrations in infant plasma. The total relative
infant dose for the combination mirtazapine and its des-
methyl metabolite was a mean of 1.9% of the maternal
weight-adjusted dose. This is a conservative estimate,
given that desmethylmirtazapine has only 5–10% of the
pharmacological activity of the parent drug [10]. Over-
all, mirtazapine contributed a mean of 80% of the oral
antidepressant dose (95% of the pharmacological activ-
ity) that the breast-fed infant is calculated to receive. In
four of the studies, a blood sample was able to be taken
from the infants (Table 1) and analysed for drug content.
Mirtazapine was detected in plasma from only one
infant (no. 2 at 1.5 µg l
1
) and desmethylmirtazapine
was not detected in any sample.
During the course of the study we collected (post-
absorption phase) 14 paired samples of fore- and hind-
milk from patients 3, 6, 7 and 8 for analysis. For
mirtazapine there was a significant increase in mean
concentration (29 µg l
1
; 95% CI for difference 18.8,
39.5) between fore- and hind-milk milk (paired t = 6.06,
P < 0.001), while for desmethylmirtazapine there was
no significant change between mean concentrations in
fore- and hind-milk. On average, the ratio of drug con-
centration in hind-milk to that in fore-milk was 2.3 (95%
CI 1.8, 2.8) for mirtazapine and 1.1 (0.9, 1.2) for desm-
ethylmirtazapine. Creamatocrit (% fat) in these paired
fore- (6.2%) and hind-milk (13.7%) samples also
Figure 1
Continued
#6
#8
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
10
20
30
40
50
60
(hrs)
061218 24
(hrs)
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
10
20
30
40
50
60
70
061218 24
(hrs)
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
20
40
60
80
100
061218 24
#5
rac-
Mirtazapine or
rac-metabolite
(mg l
1
)
0
20
40
60
80
(hrs)
061218 24
#7
Page 4
J. H. Kristensen et al.
326 63:3 Br J Clin Pharmacol
approximately doubled (mean increase 7.5%, 95% CI
for difference 4.9, 10.1, paired t = 6.2, P < 0.001).
Discussion
In the present study we measured rac-mirtazapine and
its rac-desmethyl metabolite because the racemate is the
form marketed, and because the enantiomers of both
parent drug and its metabolite contribute to overall phar-
macological activity [9, 10].
Transfer of mirtazapine into milk as measured by a
mean M/P of 1.1 was modest, but still twice that for its
desmethyl metabolite. Nevertheless, the robustness of
our M/P estimates may be questioned as we had AUC
data for only three of the patients. Co-transport of mir-
tazapine into milk with lipid was demonstrated by a
significant increase in its concentration between fore-
and hind-milk. Moreover, in line with its higher polarity,
desmethylmirtazapine transfer was not influenced by
milk lipids.
The mean absolute infant dose of mirtazapine was
low (8 µg kg
1
day
1
) compared with the mean maternal
dose of 495 µg kg
1
day
1
. The calculated mean relative
infant dose for mirtazapine plus its desmethyl metabo-
lite was some 1.9% (as mirtazapine equivalents) of the
weight-adjusted maternal dose. A relative infant dose of
<10% of the maternal weight-adjusted dose is generally
considered safe [15] and hence mirtazapine is predicted
to have a wide margin of safety in breast feeding. More-
over, none of the infants showed any drug-related
adverse effects and were achieving developmental mile-
stones. Only very low concentrations of mirtazapine
were detected in the plasma of one out of the four infants
tested. Hence, the clinical findings in the infants support
the predicted low relative infant dose. The low/undetect-
able infant plasma concentrations could in part be
explained if there is significant CYP3A4-dependent
first-pass metabolism of mirtazapine (i.e. low bioavail-
ability) in infants, as in adults [9, 18]. Overall, our data
for mirtazapine agree with, and substantially extend
those in the previous single case report, where mirtaza-
pine alone was measured in milk and plasma taken 15
and 22 h after dose [11].
One of the patients (no. 6) was taking escitalopram
as well as mirtazapine. For this patient, the calculated
relative infant dose of escitalopram plus desmethylesci-
talopram was 4% (data not shown). Hence, in consider-
ing the breast-feeding risk/benefit analysis for this
mother/baby pair, the contributions from both mirtaza-
pine and escitalopram need to be considered.
In summary, the mean relative infant dose of 1.9% for
mirtazapine plus its major desmethyl metabolite, sug-
gests that short-term mirtazapine use is safe during
breast feeding (notional level of safety <10%). Never-
theless, each decision to breast feed should always be
Table 1
Maternal dose of mirtazapine, absolute and relative infant doses and infant plasma concentrations of mirtazapine and
desmethylmirtazapine
Patient
Maternal dose
(µg kg
1
day
1
)
Mirtazapine Desmethylmirtazapine
Absolute
infant dose
(µg kg
1
day
1
)
Relative
infant
dose (%)
Infant plasma
concentration
(µg l
1
)‡
Absolute
infant dose
(µg kg
1
day
1
)
Relative
infant dose
(%)
Infant plasma
concentration
(µg l
1
)‡
Total relative
infant dose*
(%)
1 536 10.0 1.9 <1 2.7 0.5 <1 2.4
2 1967 11.2 0.6 1.5 2.5 0.1 <1 0.7
3 474 6.0 1.3 <4 1.1 0.2 <3 1.5
4 857 7.2 0.8 <1 2.6 0.3 <1 1.2
5 309 7.7 2.5 ND 1.9 0.7 ND 3.1
6 353 9.8 2.8 ND 1.5 0.4 ND 3.1
7 517 5.1 1.0 ND 0.9 0.2 ND 1.2
8 462 7.1 1.5 ND 2.3 0.5 ND 2.1
Mean 495 8.0 1.5 3.0 0.4 1.9
(95%CI) (407, 696)† (6.8, 9.8) (0.8, 2.2) (2.4, 3.6) (0.2, 0.6) (1.1, 2.7)
ND, No plasma sample available. *Expressed in mirtazapine equivalents. Median (25th & 75th percentiles). Higher limits of
detection for some samples as a result of sample volume available for assay.
Page 5
Transfer of the antidepressant mirtazapine into breast milk
Br J Clin Pharmacol 63:3 327
made on the basis of an individual risk/benefit analysis.
Long term follow-up studies of infants exposed to mir-
tazapine are still needed.
We are grateful to Organon Australia Pty Ltd for partial
financial support for the project. The balance came
from University/PathWest developmental funding. We
acknowledge Dr Megan Galbally, Dr Sandra Smith and
Dr Ken Piaggio for assistance in identifying patients.
We also acknowledge the assistance of Deborah Oost-
erbaan, Mary Wallbank and the phlebotomy staff in the
Haematology Department at the King Edward Memo-
rial Hospital for Women with sample collection on the
study days. None of the authors has any financial or
personal relationships that could potentially be per-
ceived as influencing the research described in this
manuscript.
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