VERAPAMIL

Fetal Risk Summary

Verapamil is a calcium channel inhibitor used as an antiarrhythmic agent. Reproductive studies in rats and rabbits at oral doses up to 60 mg/kg/day (6 times the human oral dose) and 15 mg/kg/day (1.5 times the human oral dose) found no evidence of teratogenicity (1). In rats, however, this dose was embryocidal, and retarded fetal growth and development, probably because of maternal toxicity (1).

Placental passage of verapamil has been demonstrated in two of six patients given 80 mg orally at term (2). Cord levels were 15.4 and 24.5 ng/mL (17% and 26% of maternal serum) in two newborns delivered at 49 and 109 minutes after verapamil administration, respectively. Verapamil could not be detected in the cord blood of four infants delivered 173–564 minutes after the dose. IV verapamil was administered to patients in labor at a rate of 2 µg/kg/minute for 60–110 minutes (3). The serum concentrations of the infants averaged 8.5 ng/mL (44% of maternal serum).

A 33-week fetus with a tachycardia of 240–280 beats/minute was treated in utero for 6 weeks with b-acetyldigoxin and verapamil (80 mg 3 times daily) (2). The fetal heart rate returned to normal 5 days after initiation of therapy, but the authors could not determine whether verapamil had produced the beneficial effect. At birth, no signs of cardiac hypertrophy or disturbances in repolarization were observed. Several other reports have described successful in utero treatment of supraventricular tachycardia with verapamil in combination with other agents (4,5 and 6). In one case, indirect therapy via the mother with verapamil, digoxin, and procainamide failed to control the fetal arrhythmia and direct fetal digitalization was required (7). In another case, verapamil, 120 mg 3 times daily, and digoxin were used successfully to control a fetal supraventricular tachycardia at 32 weeks' gestation (8). At 36 weeks' gestation, after 4 weeks of therapy, ultrasound examination showed complete resolution of both the hydropic changes and polyhydramnios, but the fetus died within 2 days. No autopsy was permitted. The authors speculated that the drug combination may have caused complete heart block (8). Maternal supraventricular tachycardia occurring in the 3rd trimester has been treated with a single 5-mg IV dose of verapamil (9). Other than the single case of fetal death in which the cause is not certain, no adverse fetal or newborn effects attributable to verapamil have been noted in the above reports.

Verapamil has been used to lower blood pressure in a woman with severe pregnancy-induced hypertension in labor (10). Fifteen milligrams were given by rapid IV injection followed by an infusion of 185 mg during 6 hours. Fetal heart rate increased from 60 to 110 beats/minute, and a normal infant was delivered without signs or symptoms of toxicity. Tocolysis with verapamil, either alone or in combination with b-mimetics, has also been described (11,12 and 13).

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 76 newborns had been exposed to verapamil during the 1st trimester (F. Rosa, personal communication, FDA, 1993). One (1.3%) major birth defect was observed (three expected), a cardiovascular defect. These data do not support an association between the drug and congenital defects.

A prospective, multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st-trimester exposure to calcium channel blockers, including 41% to verapamil, was reported in 1996 (14). Compared with controls, no increase in the risk of major congenital malformations was found. Moreover, the manufacturer has reports of patients treated with verapamil during the 1st trimester without production of fetal problems (M.S. Anderson, personal communication, GD Searle & Co., 1981). However, hypotension (systolic and diastolic) has been observed in patients after rapid IV bolus (15), and reduced uterine blood flow with fetal hypoxia is a potential risk.

Breast Feeding Summary

Verapamil is excreted into breast milk (16,17). A daily dose of 240 mg produced milk levels that were approximately 23% of maternal serum (16). Serum levels in the infant were 2.1 ng/mL but could not be detected (<1 ng/mL) 38 hours after treatment was stopped. No effects of this exposure were observed in the infant. In a second case, a mother was treated with 80 mg 3 times daily for hypertension for 4 weeks before the determination of serum and milk concentrations (17). Steady-state concentrations of verapamil and the metabolite, norverapamil, in milk were 25.8 and 8.8 ng/mL, respectively. These values were 60% and 16% of the concentrations in plasma. The investigators estimated that the breast-fed child received less than 0.01% of the mother's dose. Neither verapamil nor the metabolite could be detected in the plasma of the child. The American Academy of Pediatrics considers verapamil to be compatible with breast feeding (18).

References

1. Product information. Calan. G.D. G.D. Searle, 2000.
2. Wolff F, Breuker KH, Schlensker KH, Bolte A. Prenatal diagnosis and therapy of fetal heart rate anomalies: with a contribution on the placental transfer of verapamil. J Perinat Med 1980;8:203–8.
3. Strigl R, Gastroph G, Hege HG, Döring P, Mehring W. Nachweis von Verapamil in Mutterlichen und fetalen Blut des Menschen. Geburtshilfe Frauenheilkd 1980;40:496–9.
4. Lilja H, Karlsson K, Lindecrantz K, Sabel KG. Treatment of intrauterine supraventricular tachycardia with digoxin and verapamil. J Perinat Med 1984;12:151–4.
5. Rey E, Duperron L, Gauthier R, Lemay M, Grignon A, LeLorier J. Transplacental treatment of tachycardia-induced fetal heart failure with verapamil and amiodarone: a case report. Am J Obstet Gynecol 1985;153:311–2.
6. Maxwell DJ, Crawford DC, Curry PVM, Tynan MJ, Allan LD. Obstetric importance, diagnosis, and management of fetal tachycardias. Br Med J 1988;297:107–10.
7. Weiner CP, Thompson MIB. Direct treatment of fetal supraventricular tachycardia after failed transplacental therapy. Am J Obstet Gynecol 1988;158:570–3.
8. Owen J, Colvin EV, Davis RO. Fetal death after successful conversion of fetal supraventricular tachycardia with digoxin and verapamil. Am J Obstet Gynecol 1988;158:1169–70.
9. Klein V, Repke JT. Supraventricular tachycardia in pregnancy: cardioversion with verapamil. Obstet Gynecol 1984;63:16S–8S.
10. Brittinger WD, Schwarzbeck A, Wittenmeier KW, et al. Klinisch-Experimentelle Untersuchungen uber die Blutdruckendende Wirkung von Verapamil. Dtsch Med Wochenschr 1970;95:1871–7.
11. Mosler KH, Rosenboom HG. Neuere Moglichkeiten einer tokolytischen Behandlung in de Geburtschilfe. Z Geburtshilfe Perinatol 1972;176:85–96.
12. Gummerus M. Prevention of premature birth with nylidrin and verapamil. Z Geburtshilfe Perinatol 1975;179:261–6.
13. Gummerus M. Treatment of premature labor and antagonization of the side effects of tocolytic therapy with verapamil. Z Geburtshilfe Perinatol 1977;181:334–40.
14. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L, McElhatton PR, Schmidt MA, Koren G. The safety of calcium channel blockers in human pregnancy: a prospective, multicenter cohort study. Am J Obstet Gynecol 1996;174:823–8.
15. Rotmensch HH, Rotmensch S, Elkayam U. Management of cardiac arrhythmias during pregnancy: current concepts. Drugs 1987;33:623–33.
16. Andersen HJ. Excretion of verapamil in human milk. Eur J Clin Pharmacol 1983;25:279–80.
17. Anderson P, Bondesson U, Mattiasson I, Johansson BW. Verapamil and norverapamil in plasma and breast milk during breast feeding. Eur J Clin Pharmacol 1987;31:625–7.
18. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.