Abstract
Background:
Emedastine difumarate is a second-generation antihistamine that is more effective for nasal congestion than first-generation antihistamines. The oral form of emedastine is used for the treatment of allergic rhinitis (AR). However, data characterizing emedastine transfer across the placenta and excretion into breast milk are limited. In this case report, we assessed emedastine concentrations in maternal and neonatal blood, cord blood, and breast milk.
Materials and Methods:
After the patient provided informed consent, emedastine concentrations in maternal serum, breast milk, cord blood, and neonatal serum were measured while the mother was taking oral emedastine 2 mg once daily.
Case Report:
A 39-year-old woman with AR received emedastine during pregnancy and lactation. Her female infant was born at 37 weeks of gestation with a birth weight of 2,820 g. Emedastine concentrations in maternal serum at 11.5 and 19.0 hours after maternal dosing were 0.39 and 0.22 ng/mL, respectively. The emedastine concentration in cord blood (19.6 hours after maternal dosing) was 0.18 ng/mL. At 24 hours after delivery (44 hours after maternal dosing), emedastine was under the lower limit of quantification (<0.05 ng/mL) in the infant's serum. Emedastine concentrations in breast milk ranged from 0.06 to 0.44 ng/mL. Calculated infant doses through breast milk were much lower than the clinical dose of emedastine. The infant had normal developmental progress and no detectable drug-related adverse effects.
Conclusions:
Rates of emedastine transfer into placenta and breast milk were low. Further study is required to assess the safety of emedastine in fetuses and breastfed infants.
Introduction
Allergic rhinitis (AR), which includes nasal obstruction, sneezing, and itching, is one of the most common causes of allergy symptoms in pregnant women.1–4 Although there is no consensus on its etiology, some researchers suggest that AR during pregnancy is due to aggravation of subclinical allergy,5,6 whereas most researchers claim AR during pregnancy is caused by rising serum levels of hormones such as progesterone, estrogen, and placental growth hormone. 7
AR has been linked to snoring and an increased risk for hypertension. 8 Pregnancy-onset snoring is associated with gestational hypertension and pre-eclampsia.9,10 Furthermore, AR can substantially affect the well-being of pregnant women. Adequately managing AR symptoms during pregnancy is important to reduce maternal complications and prevent adverse fetal outcomes. 11
Antihistamines are effective for the treatment of AR. 12 Although special considerations regarding antihistamine therapy is required for pregnant and lactating women, 13 ∼10–15% of women take an antihistamine to relieve AR symptoms during pregnancy. 14
Emedastine difumarate is a second-generation antihistamine that is more effective for nasal congestion than first-generation antihistamines while causing fewer adverse reactions such as somnolence and thirst. Second-generation antihistamines are widely used for treatment of AR. Even though there are considerable epidemiological data about the safety of antihistamines in pregnant and lactating women,13,15,16 there is no published information about placental transfer of emedastine and the exposure experienced by the fetus. Furthermore, there are relatively less data on nonsedating second-generation versus first-generation antihistamines. In this case report, we assessed emedastine concentrations in maternal and infant blood, and cord blood and breast milk.
Materials and Methods
Emedastine detection
Emedastine in serum and breast milk samples were determined using a modified version of a previously validated method based on liquid chromatography tandem-mass spectrometry. 17 In brief, chromatography was performed on a 3,000 Ultimate nano-LC system interfaced with a TSQ Vantage mass spectrometer (Thermo Fisher Scientific, Tokyo, Japan). Compounds were eluted from a Unison UK-C18 column (3 μm reversed phase, 3.0 mm × 150 mm; Imtakt, Kyoto, Japan). Emedastine and naphazoline (an internal standard for emedastine) were obtained from Toronto Research Chemicals (Toronto, Canada). Acetonitrile, ammonium acetate, ethyl acetate, formic acid. Sodium hydroxide, and methanol were obtained from Thermo Fisher Scientific (Tokyo, Japan). Water was purified using the Milli-Q system (Millipore Waters, Tokyo, Japan). This method has good precision and accuracy over the concentration range of 0.05–30.0 ng/mL. The lower limit of quantification and lower limit of detection for emedastine in either breast milk or serum were 0.05 and 0.01 ng/mL, respectively.
Sample collection and preparation
The mother took a 2 mg emedastine difumarate capsule orally each day. Umbilical cord blood was collected after delivery. Serum was immediately separated with ultracentrifugation. Maternal serum samples were collected at 24.0 hours before delivery (19.0 hours after emedastine dosing) and at 16.0 hours after delivery (11.5 hours after emedastine dosing). An infant serum sample was collected at 24.0 hours after birth. Several breast milk samples were collected after administration and stored below −80°C until analysis. The timing of sample collection after emedastine dosing is presented in Table 1.
Emedastine Concentrations in Serum and Breast Milk Samples after Daily Oral Emedastine Difumarate Administration (2 mg)
EME, emedastine.
Ethics approval
This study was approved by the ethics committee of the National Center for Child Health and Development. The participant provided written informed consent.
Results
Case
A 39-year-old woman weighing 55 kg with AR was pregnant with her third child (G4P2KA1). The first child and the second child were delivered vaginally. Both were healthy. Because she had symptoms of nasal obstruction and sneezing, emedastine difumarate 2 mg capsule once daily and pranlukast hydrate 112.5 mg capsule twice daily were prescribed during her third pregnancy. During gestational week 37, a healthy female infant was born by cesarean section. The infant weighed 2,820 g at birth. Apgar scores at 1 and 5 minutes were 9 and 10, respectively. Neonatal complications such as malformation, anticholinergic symptoms, and sedation16,18 were not observed.
The infant had normal developmental progress and no detectable drug-related adverse effects at the 1-month postpartum health checkup with the primary care physician.
Emedastine concentrations in maternal serum, umbilical cord blood, and neonatal serum
Emedastine concentrations in maternal serum were 0.22 ng/mL at 24 hours before delivery (19.0 hours after the last emedastine dose) and 0.39 ng/mL at 16.0 hours after delivery (11.5 hours after the last dose). Emedastine concentration in cord blood that was collected immediately after delivery (19.6 hours after the last dose) was 0.16 ng/mL, which was 81.8% of the level in maternal serum. At 24.0 hours after delivery (44.0 hours after the mother's last dose), levels of emedastine in the infant's serum were lower than the limit of quantification (0.05 ng/mL).
Emedastine concentrations in breast milk
To assess the degree of emedastine transfer to breast milk, concentrations of emedastine in breast milk were measured several times after birth. In breast milk, emedastine concentrations at 9.3 and 12.3 hours after dosing were 0.44 and 0.13 ng/mL, respectively. At 20.3, 22.5, and 23.3 hours after dosing, concentrations were 0.09, 0.07, and 0.06 ng/mL, respectively (Table 1).
Discussion
Information on drug disposition in pregnant and lactating women is important for enabling safe and adequate treatment for mothers and their infants. In this study, we report a case of AR maintenance therapy with emedastine during pregnancy and lactation. Even though the emedastine concentration in umbilical cord blood was 81.8% of the concentration in maternal serum at ∼20 hours after administration, emedastine was rapidly eliminated from the infant's body. According to pharmacokinetic analysis, the plasma elimination half-life of emedastine ranges from 6 to 11 hours after repeated emedastine dosing of 2 mg twice daily. 19 Clearance depends on renal function. The serum half-life of emedastine in our patient was 8.5 hours. Although information about the extent of placental transfer of other antihistamines is limited, 20 most antihistamines have the potential to cross the placenta due to their low molecular weight. A previous human study indicated that high percentage of antihistamines were transferred across the placenta. 21
Although peak emedastine levels in maternal serum and breast milk were not indicated clearly by this study, mean peak emedastine levels in maternal serum ranged from 2.0 to 3.2 ng/mL, and the calculated daily infant dose ranged from 0.0003 to 0.0005 mg/kg, based on the assumption of 100% transfer ratio of emedastine into breast milk, suggesting that emedastine exposure from breast milk may have no clinically relevant effects in the infant.
Data about transfer into breast milk for other antihistamines in humans are extremely limited. However, an exclusively breastfed infant would receive extremely small amounts because drug levels in breast milk are extremely low compared with systemic levels (<0.1% of the dose).22–24 Indeed, this infant had no detectable drug-related adverse effects.
Conclusions
In this case study, emedastine was transferred from maternal blood to the fetus at concentrations that had no harmful effects on the fetus. Similarly, transfer from maternal blood to breast milk occurred at concentrations that had no harmful effects on the infant. Although the oral form of emedastine is only available in Japan and emedastine is used as eye drops in other countries, this information may be helpful to complement the information on emedastine safety for pregnant and lactating women. Further studies are needed to evaluate the potential harmful effects of exposure to emedastine in utero and during breastfeeding.
Footnotes
Authors' Contributions
J.S., H.K., N.Y., and A.M. were in charge of concept and design, data collection, article drafting, and final approval of article. A.S., T.S., and H.S. were responsible for article drafting and final approval of article. A.Y. was in charge of design and concept, critical revision of article, and final approval of article.
Acknowledgments
We thank Ms. Mariko Takagai for her expert research assistance. We are also grateful to the lactating mother for donating her precious breast milk.
Disclosure Statement
A.M. has received research grants from Astellas Pharma, Inc., and Chugai Pharmaceutical Co., Ltd., and lecture fees from Astellas Pharma, Inc., Chugai Pharmaceutical Co., Ltd., and Bristol-Myers KK. All other authors declare no conflicts of interest.
Funding Information
No funding was received for this article.