Antiarrhythmic
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Based on the very limited published information in humans, mexiletine does not appear to present a significant risk to the fetus. However, three reviews on the use of cardiovascular drugs during pregnancy caution that too few data are available to assess the safety of this agent during pregnancy (1–3).
FETAL RISK SUMMARY
Mexiletine is a local anesthetic, orally active, antiarrhythmic agent structurally similar to lidocaine. It is indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia. The drug is metabolized to inactive metabolites. Depending on hepatic or renal function, the elimination half-life is in the range of about 13–25 hours (6).
The drug is not teratogenic in pregnant mice, rats, and rabbits given doses up to and including maternal toxicity (4–6). Human pregnancy experience with mexiletine is limited to three women, one treated throughout gestation, one starting during the 14th week, and one at 32 weeks (7–9). No adverse effects attributable to mexiletine were mentioned in these reports.
A healthy 2600-g male infant was delivered at 39 weeks’ gestation (Apgar scores 9 and 10 at 1 and 5 minutes, respectively) to a 26-year-old primigravida woman who had been treated throughout her pregnancy with mexiletine (200 mg 3 times daily) and atenolol (50 mg/day) for ventricular tachycardia with multifocal ectopic beats (7). A serum mexiletine level obtained from the infant 9 hours after birth was 0.4 mcg/mL (normal therapeutic range 0.75–2.0 mcg/mL). Heart rates during a normal newborn course were 120–160 beats/minute (bpm). Postpartum, the mother continued both mexiletine and atenolol. The infant was fed breast milk only, and by 17 days of age, his weight had decreased to 2155 g. The weight loss was attributed to failure to feed and was corrected with maternal education and formula supplementation. Breastfeeding was halted at 3 months of age. Gastroesophageal reflux, presenting with seizure-like episodes but with a normal neurologic examination and electroencephalogram, was diagnosed at 8 months of age. The condition responded to corrective measures, and growth and development were appropriate at 10 months of age (7).
A 1981 report described the treatment of a 30-year-old woman with cardiac palpitations with mexiletine (600 mg/day) and propranolol (60 mg/day) starting at approximately 14 weeks’ gestation (8). A healthy infant (birth weight and sex not specified) was delivered 5 months later.
A 34-year-old woman was treated at 32 weeks’ gestation with a combination of mexiletine 200 mg 3 times daily and propranolol 40 mg 3 times daily for paroxysmal ventricular tachycardia (9). A normal male infant (birth weight not given) was delivered by spontaneous vaginal birth at 39 weeks’ gestation. Bradycardia, most likely as a result of propranolol, was noted in the infant during the first 6 hours after birth. The heart rate was 90 bpm, before increasing to a normal rate of 120 bpm. An electrocardiogram was normal. The cord blood and maternal serum mexiletine concentrations at birth were both 0.3 mcg/mL.
A 27-year-old woman was treated with mexiletine during pregnancy (10). Her initial dose was 100 mg 3 times daily but her symptoms required higher doses as her pregnancy progressed, eventually requiring 200 mg every 4 hours. At about 38 weeks’, a repeat cesarean section was performed to deliver a 3750-g male infant with Apgar scores of 4 and 9 at 1 and 5 minutes, respectively. After 5 minutes, the infant’s extremities were still blue. The low 1-minute Apgar was explained by the 9-minute general anesthesia induction to delivery time. The infant was large for gestational age and had hypoglycemia. The mother had no history of diabetes and there was no glucosuria noted during pregnancy. At delivery, maternal and fetal cord blood mexiletine concentrations were 0.6 and 0.4 mcg/mL (therapeutic concentrations are 0.7–2.0 mcg/mL), respectively. At 2 years of life, the child was developing normally (10).
A 1990 case report described the postoperative use of mexiletine (200 mg 3 times a day) in a 27-year-old woman who had undergone an aortic valve replacement under general anesthesia at 29 weeks’ gestation (11). A normal 2510-g female infant was born by cesarean section at 28 weeks’ with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. The postoperative course after delivery was uneventful (11).
BREASTFEEDING SUMMARY
Mexiletine is excreted into breast milk in concentrations exceeding those in the maternal serum (8,9). Three cases have been reported in which a nursing infant was exposed to the drug via the milk with drug levels determined in two of these cases. All three infants had been exposed to mexiletine in utero, and no adverse effects attributable to the drug were noted.
Milk and serum mexiletine concentrations in a woman described above, who was taking 600 mg/day in divided doses, were 0.6 and 0.3 mcg/mL, respectively, 2 days postpartum, and 0.8 and 0.7 mcg/mL, respectively, 6 weeks after delivery (9). These levels represented milk:plasma ratios of 2.0 and 1.1, respectively. Mexiletine was not detected in serum samples from the breastfed infant at either sampling time, nor were adverse effects observed in the infant. A second report, appearing 1 year later, described the excretion of the antiarrhythmic agent into breast milk of a woman also taking 600 mg/day in divided doses (8). Again, no adverse effects were noted in the breastfed infant. Twelve paired milk and serum levels, collected from the mother between the 2nd and 5th postpartum days, yielded peak concentrations of 0.959 mcg/mL in the milk compared with 0.724 mcg/mL in the serum, a ratio of 1.32 (mean ratio 1.45, range 0.78–1.89) (8).
Failure to feed was observed in a wholly breastfed infant whose mother was taking mexiletine (600 mg/day) and atenolol (50 mg/day) (7). The infant’s weight dropped from 2600 g at birth to 2155 g at 17 days of age. An acceptable growth curve was obtained with maternal education and formula supplementation for the next 2.5 months, after which breastfeeding was stopped (7).
The American Academy of Pediatrics classifies mexiletine as compatible with breastfeeding (12).
References
1.Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:1357–63.
2.Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy. Current concepts. Drugs 1987;33:623–33.
3.Brodsky M, Doria R, Allen B, Sato D, Thomas G, Sada M. New-onset ventricular tachycardia during pregnancy. Am Heart J 1992;123:933–41.
4.Matsuo A, Kast A, Tsunenari Y. Reproduction studies of mexiletine hydrochloride by oral administration. Iyakuhin Kenkyu 1983;14:527–49. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:427.
5.Nishimura M, Kast A, Tsunenari Y. Reproduction studies of mexiletine hydrochloride by intravenous administration. Iyakuhin Kenkyu 1983;14:550–70. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:427.
6.Product information. Mexiletine. Watson Laboratories, 2006.
7.Lownes HE, Ives TJ. Mexiletine use in pregnancy and lactation. Am J Obstet Gynecol 1987;157:446–7.
8.Lewis AM, Patel L, Johnston A, Turner P. Mexiletine in human blood and breast milk. Postgrad Med J 1981;57:546–7.
9.Timmis AD, Jackson G, Holt DW. Mexiletine for control of ventricular dysrhythmias in pregnancy. Lancet 1980;2:647–8.
10.Gregg AR, Tomich PG. Mexilitene use in pregnancy. J Perinatol 1988 Winter;8:33–5.
11.Ben-Ami M, Battino S, Rosenfeld T, Marin G, Shalev E. Aortic valve replacement during pregnancy—a case report and review of the literature. Acta Obstet Gynecol Scand 1990;69:651–3.
12.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.