Transfer of Mexiletine into Breast Milk: A Case Report

Abstract

Background:

Mexiletine is a class 1B antiarrhythmic agent, used to treat ventricular arrhythmias, and noncardiac-related problems such as myotonia. Limited safety data are available on the transfer of this drug into breast milk.

Case Report:

We report the case of a woman diagnosed with myotonia congenita who breastfed two children after two consecutive pregnancies. During the breastfeeding of the first and the second infant, she collected, respectively, five and seven samples at 0, 2, 4, 6, and 8 hours and 0, 1, 2, 3, 4, 6, and 8 hours after taking 200 mg of mexiletine thrice daily for seven doses. One week after the collection, samples were analyzed with a validated liquid chromatography tandem mass spectrometry method. No side effect was observed in either child according to the mother.

Results:

Using the mean milk concentrations, it is estimated that an exclusively breastfed infant would receive a maximum of 5.14% of the initial pediatric mexiletine dosage. We calculated a maximum of 2.67% for the first infant in our case, considering a nonexclusive breastfeeding. Maximal concentrations were observed 1–2 hours after the dose of mexiletine. Results seem to be in accordance with the two cases previously published.

Conclusions:

Mexiletine transfers into breast milk in low levels. However, results are obtained from only one woman. Therefore, caution should be used when mexiletine is prescribed to breastfeeding women. More cases are needed to evaluate the interindividual variability and to guide women regarding breastfeeding with mexiletine.

Introduction

Mexiletine is a class 1B antiarrhythmic agent, which blocks the fast sodium channels in cardiac tissues, especially the Purkinje network, without involvement of the autonomic system.¹ This drug was approved to treat ventricular arrhythmias by Health Canada and the U.S. Food and Drug Administration in December 1985.^2,3 It is also used to reduce myotonia by blocking the sodium channels involved in the contraction and relaxation of muscles.⁴ Only three articles have been published, in 1980,⁵ 1981,⁶ and 1987,⁷ on the transfer of mexiletine into breast milk or on its use during breastfeeding in women treated for ventricular tachycardia.

In the first case report in 1980, two breast milk samples were collected, at 2 days and 6 weeks after delivery, from a woman who was taking 200 mg of mexiletine thrice daily. There is no information about the interval between the dose and the collection of the milk. Concentrations of 0.6 and 0.8 mg/L were measured. With these milk concentrations, we can estimate that an infant exclusively breastfed with 150 mL/(kg·day) would take 0.09–0.12 mg/(kg·day) of mexiletine by milk. This corresponds to 3% of the initial pediatric dosage of 4 mg/(kg·day) that has been used to treat children of 3 months or older.⁸ The child was born healthy except for a bradycardia during the first 6 hours of life, probably secondary to in utero exposure to propranolol. He was breastfed for at least 6 weeks, but there is no information on the exact duration of breastfeeding and his health during breastfeeding.⁵

In the second report in 1981, the authors obtained 12 samples of breast milk at different times between the second and the fifth day after delivery from a woman who was also taking 200 mg of mexiletine thrice daily. The newborn was healthy at birth. A mean peak concentration of 0.96 mg/L was measured in breast milk.⁶ This time, the absolute infant dose would be 0.14 mg/(kg·day) and the percentage of the pediatric dose would be 3.5%. The interval between the dose and the collection is unknown and it is not mentioned whether the infant was breastfed or not.

Finally, in the third case report in 1987, no breast milk sample was collected. The authors observed that the breastfed infant was in good health 10 months after the delivery. The infant has been breastfed until 3 months old. At 17 days of life, a weight loss of 17% compared with his birth weight was noticed, which was felt to be caused by an insufficient feeding, and a formula supplementation was needed, but the authors did not make any correlation with the use of mexiletine. The woman was taking 250 mg of mexiletine thrice daily.⁷

Mexiletine has the characteristics of a drug that could pass into breast milk; it has a moderate protein binding (70%), is lipophilic (logp = 1.3), is a weak base (pKa = 9.3), is a small molecule (179 daltons), and has a long half-life (10–15 hours).⁹ Since there is little information about the transfer of mexiletine into breast milk, it is challenging for clinicians to provide guidance to their patients on the use of this medication during breastfeeding. Therefore, it is important to report every case of mexiletine quantification in breast milk. In our case, we quantified mexiletine in breast milk for an 8-hour period after two pregnancies. The patient was taking 200 mg three times a day.

Case Report

The patient

When the first milk sampling was done, the patient was a 32-year-old woman weighing 79 kg. She was diagnosed with an autosomal dominant myotonia congenita. Mexiletine 200 mg orally thrice daily and pregabalin 75 mg orally twice daily were the medications used to attenuate the symptoms and the pain, at this time. Other medications taken by the patient were venlafaxine 150 mg orally once daily for generalized anxiety, dexlansoprazole 60 mg orally once daily for gastric pain due to mexiletine, and acetaminophen 500 mg orally four times daily for pain.

During her first pregnancy, she stopped acetaminophen, dexlansoprazole, mexiletine, and pregabalin and lowered her dose of venlafaxine to 75 mg daily. During breastfeeding, she first resumed dexlansoprazole, which was changed for esomeprazole 20 months after delivery due to intestinal pain. For breast milk sampling purposes, she took 200 mg of mexiletine thrice daily for a total of seven doses, 9 months after delivery. A few weeks after sampling, she started again her treatment by taking 200 mg of mexiletine twice a day.

Two years after the first sampling, the patient had a new pregnancy. At this time, a clinical study was ongoing in Montreal to quantify several drugs in breast milk, including mexiletine. The patient was, therefore, enrolled in this study after giving a written informed consent. During breastfeeding, she was only taking venlafaxine 75 mg. Again, she decided to take seven doses of mexiletine 200 mg every 8 hours just before the breast milk sampling, 3 months after delivery.

The infants

The first baby was born healthy and was exclusively breastfed. At first, she was only exposed to the drug during the sampling. At this time, she was 9 months old, she was breastfed every 2–3 hours and she was eating solid food. The mother reported no adverse effect for the infant during the sampling. A few weeks later, the infant was re-exposed to the medication as the mother restarted her treatment. At the latest update, the infant was 2 years old, breastfed three to five times a day, and no adverse effect was reported by the mother during breastfeeding.

The second baby was also born healthy and was partially breastfed until the time of sampling (at least 75%). This baby was only exposed to the drug during the sampling at 3 months of age. According to a questionnaire on the newborn's health, the mother reported no adverse effect during the exposure.

Methods

Sampling

For the first sampling period, at 9 months postpartum, five samples of breast milk were collected for an 8-hour period to calculate the area under the curve (AUC) of the drug concentration in function of time and determine the pharmacokinetics of mexiletine in human milk. The first sample was collected a few minutes before the seventh dose of 200 mg and the four others were collected 2, 4, 6, and 8 hours after the dose. The second and third samples were collected to correlate with the estimated peak plasma concentration (C_max) that occurs between 2 and 4 hours.¹⁰

For the second sampling period, at 3 months postpartum, seven breast milk samples were collected for an 8-hour period. Samples were collected few minutes before the seventh 200 mg dose, 1, 2, 3, 4, 6, and 8 hours after the dose.

All the samples were frozen by the patient, then directly delivered to the Université de Montréal and frozen at −80°C in the following days.

Sample analysis

One week after their collection, samples were analyzed with a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method described in detail previously, using an electrospray ionization source operated in the positive ion mode.¹¹ Before the analysis, samples were diluted 1:20 in blank milk to fit in the calibration range. Breast milk samples, containing an internal standard, were previously extracted by protein precipitation with acetonitrile and methanol. Detection was carried out in multiple reaction monitoring mode with optimized voltage settings for MRM transitions (180 → 58), collision energy (30 eV) and declustering potential (30 V).

A Kinetex-C8 column was used for the chromatographic separation. A gradient of mobile phases A: water with 0.1% formic acid and B: acetonitrile with 0.1% formic acid was used at a flow rate of 0.75 mL/min. Calibration curves were prepared in blank breast milk, ranging from 0.5 to 500 ng/mL. The lower limits of detection and quantification of the method were 0.2 and 0.5 ng/mL, respectively. Interday variability of the method for quality controls ranged from 3.79% to 8.43%, recovery was 107.2% and matrix effect was 91.4%. Finally, there was no significant carryover. The method was fully validated. Accuracy, precision, carryover, selectivity, matrix effect, recovery, and stability were tested during method validation.

Newborn exposure

The AUC was calculated for an 8-hour period using a trapezoidal method. Then, the mean concentration was obtained by dividing the AUC by 8. This result can be multiplied by the daily milk intake, assumed to be a maximum of 75 mL/(kg·day) as the first child was not exclusively breastfed or 150 mL/(kg·day) as the exact volume of milk ingested by the second child was unknown but close to an exclusive breastfeeding, to obtain the absolute infant dose [in mg/(kg·day)]. Therefore, it is possible to calculate the relative infant dose by dividing the absolute infant dose by the maternal weight adjusted dose.

In addition, the ratio of the pediatric dose was obtained by dividing the absolute infant dose by the initial pediatric dose [4 mg/(kg·day)].^8,12 These values represent the fraction of the maternal dose (adjusted to weight) or of the pediatric dose that the newborn ingests. When a pediatric dose is available, it is preferable to calculate the ratio of the pediatric dose to have a better view of the infant's exposure. To estimate the maximum infant exposure, we also use the C_max in breast milk and calculate the maximal absolute infant dose. This calculation assumes that the newborn is constantly exposed to the C_max.

Results

Mexiletine concentration in breast milk samples are shown in Table 1. Table 2 shows our results for the pharmacokinetic properties of mexiletine in breast milk considering the mean and the maximal concentration of drug in breast milk.

Table 1.

Concentration of Mexiletine in Five and Seven Different Milk Samples for Children 1 and 2

Sample	Time after the last dose, hours:minutes	Milk concentration, mg/L
1^a	−0:13	1.06
2^a	+2:13	1.90
3^a	+4:04	1.38
4^a	+6:00	1.28
5^a	+8:04	1.24
1^b	+0:00	0.89
2^b	+1:00	2.82
3^b	+2:00	1.22
4^b	+3:00	1.54
5^b	+4:00	1.25
6^b	+6:00	1.05
7^b	+8:00	0.96

Samples for child 1.

Samples for child 2.

Table 2.

Pharmacokinetic Parameters of Mexiletine 200 mg Thrice Daily in a Breastfeeding Woman

Pharmacokinetic parameters	Results child 1	Results child 2
AUC_{0–8 hours}, mg/(h·L)	11.41	10.96
Milk T_max, hours	2	1
Breast milk C_avg, mg/L	1.43	1.37
Daily infant dose, mg/(kg·day)^a	0.11	0.21
Maternal dose, mg/(kg·day)	7.59	7.79
Estimated % of the pediatric dose	2.67^b	5.14^b
RID, %	1.41	2.64
Breast milk C_max, mg/L	1.90	2.82
Daily infant dose considering the maximal concentration, mg/(kg·day)^a	0.14	0.42
% of the pediatric dose considering the maximal concentration	3.56^b	10.58^b
RID considering the maximal concentration, %	1.88	5.43

Estimated mexiletine dose ingested by the breastfed infants using the AUC and assuming a daily milk intake of 75 mL/(kg·day) for child 1 and 150 mL/(kg·day) for child 2.

Considering an initial pediatric dose of 4 mg/(kg·day).

AUC, area under the drug concentration versus time curve; C_avg, average drug concentration over the time interval; C_max, maximum drug concentration; RID, relative infant dose compared with maternal weight-adjusted dose; T_max, time at which maximum drug concentration is reached.

Discussion

To our knowledge, this is the first time that mexiletine was quantified in breast milk for an 8-hour period after the dose using multiple samples. Thus, it is possible to observe the variation of the concentration of mexiletine as a function of time. Indeed, this allows to estimate a more representative breast milk exposure of the newborn to the drug. We measured a mean concentration of 1.43 mg/L and a C_max of 1.90 mg/L 2 hours after a 200 mg dose for the first child. Owing to a more intensive sampling protocol for the second child, we obtained a mean concentration of 1.37 mg/L and a C_max of 2.82 mg/L 1 hour after a 200 mg dose.

In both cases, concentrations of mexiletine in breast milk were similar suggesting little intraindividual variability. These results indicate that the milk C_max occurs just before the plasma C_max of mexiletine, which is between 2 and 4 hours.¹⁰ However, the plasma T_max was not assessed for this woman; thus, the plasma C_max might have occurred at the same time as the milk C_max due to interindividual variability. According to the mexiletine monograph, the C_max of mexiletine in human blood after a single 200 mg oral dose is between 0.292 and 0.337 mg/L, which is lower than the maximal concentrations in breast milk that we measured.¹

However, the plasma C_max of mexiletine is expected to be higher after the administration of multiple doses and the achievement of steady state. Lewis et al. found a milk to plasma ratio of 1.45, whereas Timmis et al. found milk to plasma ratios of 1.14 and 2.0, which indicate a higher concentration of mexiletine in breast milk than in plasma.^5,6 Those results are in agreement with the physicochemical properties of the drug. Mexiletine is a weak base; thus, it can accumulate in the milk compartment, as the pH of milk is lower than the pH of plasma.¹³ Finally, the other drugs taken by the mother during the sampling, venlafaxine and dexlansoprazole, are not known to affect mexiletine maternal plasma concentrations.¹

Using an initial pediatric dose of 4 mg/(kg·day), we estimated a ratio of the pediatric dose of 2.67% based on the mean concentration and 3.56% based on the C_max for the first child. However, this value is specific to this infant. Indeed, she was not exclusively breastfed, which reduces the infant's exposure to the drug. The mean ratio of the pediatric dose for the second child for whom the daily milk intake was evaluated to 150 mL/(kg·day), as it was not possible to measure the exact volume of milk ingested by this newborn,¹⁴ would be 5.14% and the maximal ratio of the pediatric dose would be 10.58%. Although those values represent the exposure of newborns exclusively breastfed, they overestimate the exposure of the second child as she was partially breastfed (at least 75%).

In all cases, those values are under or at the limit of the theoretical limit of 10%, under which there is low probability of adverse effects for a healthy infant exclusively breastfed and born at term.¹⁵ Nevertheless, mexiletine could accumulate in children before 1–2 months old as it is metabolized by the CYP2D6.¹⁶ Indeed, the hepatic metabolism of infants is immature at this time of life and the CYP2D6 activity is low.¹⁷ Therefore, the mother was asked to wait 3 months after delivery to restart her mexiletine treatment. No adverse effect was observed during sampling in either child. However, the exposure of the infants to the drug was limited to the time of sampling (3 days). Also, no adverse effect was observed by the mother when the first 2-year-old child was breastfed three to five times a day starting at 10 months, according to the latest update. Unfortunately, no samples were taken at this time.

Another limitation of our study would be the limited number of doses that the mother took before the sampling. Seven doses were calculated to be at steady state considering a half-life of 10 hours. As the half-life may be longer (up to 15 hours), there is a possibility that she was not completely at steady state. Indeed, according to our results, in both sampling, concentrations were higher 8 hours after the dose (1.24 and 0.96 mg/L) than just before the dose (1.06 and 0.89 mg/L), suggesting that steady state might not have been completely achieved. Therefore, measured concentrations of mexiletine might be lower than it would have been at steady state and the newborn exposure might be underestimated.

In conclusion, we were able to characterize the transfer of mexiletine in breast milk as a function of time. To our knowledge, this is the first time that mexiletine was quantified in breast milk samples of a woman treated for myotonia. The results seem to be reproducible and in accordance with those previously published. However, they are obtained from a single woman and the possible interindividual variability in the transfer of the medication in breast milk, such as the weight of the mother or the number of feeds per day, needs to be considered. If mexiletine is prescribed to a woman during breastfeeding, clinicians should monitor the infant for potential adverse effects observed on children such as nausea, vomiting, and heartburn.¹⁸

Footnotes

Acknowledgment

We are thankful to the woman who gave samples of her milk twice for our analysis without which this case report could not have been possible.

Authors' Contributions

Conceptualization, methodology, validation, formal analysis, and writing—original draft by A.M. Conceptualization, methodology, formal analysis, writing—review and editing, supervision, and project administration by C.M. Conceptualization, methodology, and writing—review and editing by M.J. Resources and writing—review and editing by S.C. Conceptualization, methodology, resources, writing—review and editing, supervision, project administration, and funding acquisition by G.L. Conceptualization, methodology, writing—review and editing, supervision, project administration, and funding acquisition by E.F.

Disclosure Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Funding Information

Anaëlle Monfort and Ema Ferreira received funding from Chaire Pharmaceutique Famille Louis-Boivin to develop and validate the LC-MS/MS method and collect the samples. Also, Anaëlle Monfort received funding from the Canadian Institutes of Health Research and the Faculty of Pharmacy of the Université de Montréal. The other authors declared receiving no financial support.

References

Teva-Mexiletine. Teva. Teva Canada Limited. [Internet]. Toronto, ON; 2016. [Cited September 8, 2021] Available from: https://pdf.hres.ca/dpd_pm/00035807.PDF [Last accessed: February 14, 2023].

Drugs Product Database (DPD) [Internet]. Health Canada [2002]. [Cited September 8, 2021]—DIN:00599964, Mexitil cap 200 mg; [about 1 p.]. By entering Mexitil in the Search box. DIN: 00599964. Available from: https://health-products.canada.ca/dpd-bdpp/index-eng.jsp [Last accessed: February 14, 2023].

FDA. Center for Drug Evaluation and Research: Approval Package for: Mexitil; 1985. [Cited September 8, 2021]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/018873Orig1s000rev.pdf [Last accessed: February 14, 2023].

Stunnenberg

, Raaphorst

, Groenewoud

, et al. Effect of mexiletine on muscle stiffness in patients with nondystrophic myotonia evaluated using aggregated N-of-1 Trials. JAMA, 2018; 320(22):2344–2353.

Timmis

, Jackson

, Holt

. Mexiletine for control of ventricular dysrhythmias in pregnancy. Lancet, 1980; 2(8195 Pt 1):647–648.

Lewis

, Patel

, Johnston

, et al. Mexiletine in human blood and breast milk. Postgrad Med J, 1981; 57(671):546–547.

Lownes

, Ives

. Mexiletine use in pregnancy and lactation. Am J Obstet Gynecol, 1987; 157(2):446–447.

Washington University School of Medicine in St. Louis. Department of Pediatrics. [Internet]; 2021. [Cited September 8, 2021]—Mexiletine. Available from: https://pediatriccardiology.wustl.edu/items/mexiletine/ [Last accessed: March 29, 2023].

Hashimoto

. Mexiletine. Cardiovasc Drug Rev, 1986; 4(1):141–161.

10.

Mexiletine. European Medicines Agency. [Internet]. London; 2018. [Cited September 8, 2021]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/namuscla-epar-public-assessment-report_en.pdf [Last accessed: February 14, 2023].

11.

Monfort

, Jutras

, Martin

, et al. Simultaneous quantification of 19 analytes in breast milk by liquid chromatography-tandem mass spectrometry (LC-MS/MS). J Pharm Biomed Anal, 2021; 10(204):114236.

12.

Hotham

, Hotham

. Drugs in breastfeeding. Aust Prescr, 2015; 38(5):156–159.

13.

Breitzka

, Sandritter

, Hatzopoulos

. Principles of drug transfer into breast milk and drug disposition in the nursing infant. J Hum Lact, 1997; 13(2):155–158.

14.

Wilson

. Determination and consequences of drug excretion in breast milk. Drug Metab Rev, 1983; 14(4):619–652.

15.

Anderson

, Sauberan

. Modeling drug passage into human milk. Clin Pharmacol Ther, 2016; 100(1):42–52.

16.

Mexitil. Boehringer Ingelheim. [Internet]. Ridgefield, CT; 2003. [Cited August 25, 2020]. Available from: https://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Mexitil%20Caps/Mexitil.pdf [Last accessed: February 14, 2023].

17.

Gow

, Ghabrial

, Smallwood

. Neonatal hepatic drug elimination. Pharmacol Toxicol, 2001; 88:3–15.

18.

Kerin

, Aragon

, Marinescu

, et al. Mexiletine. Long-term efficacy and side effects in patients with chronic drug-resistant potentially lethal ventricular arrhythmias. Arch Intern Med, 1990; 150(2):381–384.