MEXILETINE

Fetal Risk Summary

Mexiletine is a local anesthetic, orally active, antiarrhythmic agent structurally similar to lidocaine. The drug is not teratogenic in pregnant mice, rats, and rabbits given doses up to and including maternal toxicity (1,2 and 3). 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 (4,5 and 6). 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 (4). A serum mexiletine level obtained from the infant 9 hours after birth was 0.4 µg/mL (normal therapeutic range 0.75–2.0 µg/mL) (4). Heart rates during a normal newborn course were 120–160 beats/minute. 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. Breast feeding 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.

A 1981 report described the treatment of a 30-year-old woman with cardiac palpitations with 600 mg/day of mexiletine and 60 mg/day of propranolol starting at approximately 14 weeks' gestation (5). 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 (6). 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 beats/minute, before increasing to a normal rate of 120 beats/minute. An electrocardiogram was normal. The cord blood and maternal serum mexiletine concentrations at birth were both 0.3 µg/mL.

Based on the very limited published information in animals and 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 (7,8 and 9).

Breast Feeding Summary

Mexiletine is excreted into human breast milk in concentrations exceeding those in the maternal serum (5,6). 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. The American Academy of Pediatrics considers mexiletine to be compatible with breast feeding (10).

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 µg/mL, respectively, 2 days postpartum, and 0.8 and 0.7 µg/mL, respectively, 6 weeks after delivery (6). These levels represented milk:plasma ratios of 2.0 and 1.1, respectively. Mexiletine was not detected in serum samples from the breast-fed 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 (5). Again, no adverse effects were noted in the breast-fed infant. Twelve paired milk and serum levels, collected from the mother between the 2nd and 5th postpartum days, yielded peak concentrations of 0.959 µg/mL in the milk compared with 0.724 µg/mL in the serum, a ratio of 1.32 (mean ratio 1.45, range 0.78–1.89).

Failure to feed was observed in a wholly breast-fed infant whose mother was taking mexiletine (600 mg/day) and atenolol (50 mg/day) (4). 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 breast feeding was stopped (4).

References

1. 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.
2. Nishimura M, Kast A, Tsunenari Y. Reproduction studies of mexiletine hydrochloride by intravenous administration. Ikakuhin Kenkyu 1983;14:550–70. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:427.
3. Product information. Mexitil. Boehringer Ingelheim, 1992.
4. Lownes HE, Ives TJ. Mexiletine use in pregnancy and lactation. Am J Obstet Gynecol 1987;157:446–7.
5. Lewis AM, Patel L, Johnston A, Turner P. Mexiletine in human blood and breast milk. Postgrad Med J 1981;57:546–7.
6. Timmis AD, Jackson G, Holt DW. Mexiletine for control of ventricular dysrhythmias in pregnancy. Lancet 1980;2:647–8.
7. Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:1357–63.
8. Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy. Current concepts. Drugs 1987;33:623–33.
9. 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.
10. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.