Risk Factor: CM
Class: Cardiovascular drugs/ Cardiac drugs
Fetal Risk Summary
No reports linking the use of disopyramide with congenital defects in humans or animals have been located. Maternal toxicity (decreased food consumption and weight gain), embryotoxicity (decreased number of implantation sites), and fetotoxicity (decreased growth and pup survival) were observed in pregnant rats dosed at 250 mg/kg/day (20 or more times the recommended human dose of 12 mg/kg/day, assuming a patient weighing at least 50 kg [RHD]) (1). Increased resorption rates occurred in rabbits dosed at 60 mg/kg/day (5 or more times the RHD), but implantation rates, fetal growth, and offspring survival were not evaluated.
At term, a cord blood level of 0.9 g/mL (39% of maternal serum) was measured 6 hours after a maternal 200-mg dose (2). A 27-year-old woman took disopyramide throughout a full-term gestation, 1350 mg/day for the last 16 days, and delivered a healthy, 2920-g female infant (2). Concentrations of disopyramide and the metabolite N-monodesalkyl disopyramide in the cord and maternal serum were 0.7 and 0.9 g/mL, and 2.7 and 2.1 g/mL, respectively. The cord:maternal ratios for the parent drug and metabolite were 0.26 and 0.43, respectively (3). In a separate study, the mean fetal:maternal total plasma ratio was 0.78 when the mother’s plasma concentration was within the therapeutic range of 2.05.0 g/mL (4).
Disopyramide has been used throughout other pregnancies without evidence of congenital abnormalities or growth retardation (2,5,6) (M.S. Anderson, personal communication, G.D. Searle and Company, 1981). Early onset of labor has been reported in one patient (7). The mother, in her 32nd week of gestation, was given 300 mg orally, followed by 100 or 150 mg every 6 hours for posterior mitral leaflet prolapse. Uterine contractions, without vaginal bleeding or cervical changes, and abdominal pain occurred 12 hours after each dose. When disopyramide was stopped, symptoms subsided over the next 4 hours. Oxytocin induction 1 week later resulted in the delivery of a healthy infant. The oxytocic effect of disopyramide was studied in 10 women at term (8). Eight of the 10 women, treated with 150 mg every 6 hours for 48 hours, delivered within 48 hours, compared to none in a placebo group. In one patient, use of 200 mg twice daily during the 18th and 19th weeks of pregnancy was not associated with uterine contractions or other observable adverse effects in the mother or fetus (9). Most reviews of antiarrhythmic drug therapy consider the drug probably safe during pregnancy (5,10), but one does not recommend it for routine therapy (11), and one warns of its oxytocic effects (12).
Breast Feeding Summary
Disopyramide is excreted into breast milk (3,6,13,14). In a woman taking 200 mg 3 times daily, samples obtained on the 5th8th days of treatment revealed a mean milk:plasma ratio of 0.9 for disopyramide and 5.6 for the active metabolite (13). Neither drug was detected in the infant’s plasma. In a second case, a mother was taking 450 mg of disopyramide every 8 hours 2 weeks postpartum (3). Milk and serum samples were obtained at 0, 2, 4, and 8 hours after the dose following an overnight fast. Milk concentrations of disopyramide and its metabolite, N-monodesalkyl disopyramide, ranged from 2.64.4 g/mL and from 9.612.3 g/mL, respectively. In both cases, the lowest levels occurred at the 8-hour sampling time. The mean milk:plasma ratios for the two were 1.06 and 6.24, respectively. Disopyramide was not detected in the infant’s serum (test sensitivity 0.45 g/mL), but both disopyramide and the metabolite were found in the infant’s urine, 3.3 and 3.7 g/mL, respectively. A brief 1985 report described a woman taking 100 mg five times a day throughout pregnancy who delivered a normal female infant (6). On the 2nd postpartum day and 2 hours after a dose, paired milk and serum sample were obtained. The concentrations of disopyramide in the aqueous phase of the milk and the serum were 4.0 and 10.3 mol/L, respectively, a milk:serum ratio of 0.4. The same ratio was obtained 2 weeks later with samples drawn 3 hours after a dose and levels of 5.0 and 11.5 mol/L, respectively. No disopyramide was found in the infant’s serum (limit of test accuracy 1.5 mol/L) during the second sampling. A woman taking 200 mg twice daily had milk and serum samples drawn before and 3.5 hours after a dose (14). The concentrations in the serum were 3.7 and 5.5 mol/L, and those in the milk were 1.7 and 2.9 mol/L, respectively. The milk:serum ratios were 0.46 before and 0.53 after the dose. No adverse effects were noted in the nursing infants in any of the above cases. The American Academy of Pediatrics considers disopyramide to be compatible with breast feeding (15).
- Product information. Norpace. G. D. Searle and Company, 2000.
- Shaxted EJ, Milton PJ. Disopyramide in pregnancy: a case report. Curr Med Res Opin 1979;6:702.
- Ellsworth AJ, Horn JR, Raisys VA, Miyagawa LA, Bell JL. Disopyramide and N-monodesalkyl disopyramide in serum and breast milk. Drug Intell Clin Pharm 1989;23:567.
- Echizen H, Nakura M, Saotome T, Minoura S, Ishizaki T. Plasma protein binding of disopyramide in pregnant and postpartum women, and in neonates and their mothers. Br J Clin Pharmacol 1990;29:42330.
- Rotmensch HH, Elkayam U, Frishman W. Antiarrhythmic drug therapy during pregnancy. Ann Intern Med 1983;98:48797.
- MacKintosh D, Buchanan N. Excretion of disopyramide in human breast milk. Br J Clin Pharmacol 1985;19:8567.
- Leonard RF, Braun TE, Levy AM. Initiation of uterine contractions by disopyramide during pregnancy. N Engl J Med 1978;299:845.
- Tadmor OP, Keren A, Rosenak D, Gal M, Shaia M, Hornstein E, Yaffe H, Graff E, Stern S, Diamant YZ. The effect of disopyramide on uterine contractions during pregnancy. Am J Obstet Gynecol 1990;162:4826.
- Stokes IM, Evans J, Stone M. Myocardial infarction and cardiac arrest in the second trimester followed by assisted vaginal delivery under epidural analgesia at 38 weeks gestation. Case report. Br J Obstet Gynaecol 1984;91:1978.
- Tamari I, Eldar M, Rabinowitz B, Neufeld HN. Medical treatment of cardiovascular disorders during pregnancy. Am Heart J 1982;104:135763.
- Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy: current concepts. Drugs 1987;33:62333.
- Ward RM. Maternal drug therapy for fetal disorders. Semin Perinatol 1992;16:1220.
- Barnett DB, Hudson SA, McBurney A. Disopyramide and its N-monodesalkyl metabolite in breast milk. Br J Clin Pharmacol 1982;14:3102.
- Hoppu K, Neuvonen PJ, Korte T. Disopyramide and breast feeding. Br J Clin Pharmacol 1986;21:553.
- Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:13750.