NICARDIPINE

Fetal Risk Summary

Nicardipine is a calcium channel-blocking agent used in the treatment of angina and hypertension. The drug has also been used as a tocolytic in premature labor.

Dose-related embryotoxicity, but not teratogenicity, was observed in reproduction studies using IV nicardipine in rats and rabbits (1). Embryotoxic doses were about 2.5 and 0.5 times, respectively, the maximum recommended human dose (MRHD). At 50 times the MRHD in rats, dystocia, reduced birth weights, reduced neonatal survival, and reduced neonatal weight gain were noted (1). In one type of rabbit, but not in another, high doses (about 75 times the MRHD) were embryocidal (1). Two studies with rats reported that in utero exposure had no effect on postnatal function or subsequent fertility (2,3).

Nicardipine 20 µg/kg/minute was infused for 2 minutes in 15 near-term ewes given angiotensin II 5 µg/minute (4). Transient bradycardia was observed in the fetuses, followed by hypercapnia and acidemia. These changes were associated with a decrease in fetal placental blood flow and an increase in fetal vascular resistance, and five fetuses died 65 minutes after nicardipine was given. In the second part of this study in the pregnant ewe, nicardipine was found to reverse maternal angiotensin II–induced systemic vasoconstriction, including that of the renal and endomyometrial vascular beds, but it caused a significant increase in placental vascular resistance (5).

The use of nicardipine as a tocolytic agent was first investigated in an experiment using excised rabbit uterus and in laboring (either spontaneous or induced) rats (6). In both species, the calcium channel blocker was effective in abolishing uterine contractions. A 1983 study investigated the effect of nicardipine and nifedipine on isolated human pregnant-term and nonpregnant myometrium (7). Nicardipine was a more potent tocolytic than nifedipine in pregnant myometrium, but its onset of action was slower.

Because the cardiovascular and myometrial responses of pregnant rabbits are similar to those observed in human pregnancies (8), a series of studies was conducted in the rabbit with nicardipine to determine its effectiveness as a tocolytic agent and its safety for the mother and the fetus (8,9 and 10). A statistically significant inhibition of uterine contractions was recorded in each study, but this effect was accompanied by maternal tachycardia, an increase in cardiac output, a drop in both diastolic and systolic blood pressure and mean arterial pressure, and a decrease in uteroplacental blood flow. The authors of these studies cautioned that further trials were necessary because the decrease in uteroplacental blood flow would seriously jeopardize the fetus (9,10).

In a study to determine the tocolytic effects of nicardipine in a primate species, pregnant rhesus monkeys with spontaneous uterine contractions were treated with an IV bolus of 500 µg, followed by a continuous infusion of 6 µg/kg/minute for 1 hour (11). Placental transfer of nicardipine was demonstrated with peak fetal concentrations ranging from 7 to 35 ng/mL compared with maternal peak levels of 175–865 ng/mL. Although a marked tocolytic effect was observed, significant acidemia and hypoxemia developed in the fetuses.

The tocolytic effects of nicardipine have been reported (12,13 and 14). The agent compared favorably to albuterol (12) and magnesium sulfate (13,14). No adverse effects in the newborns attributable to nicardipine were observed.

The direct effects of nicardipine on the fetus were investigated in a study using fetal sheep (15). Infusions of nicardipine, either 50 µg or 100 µg, had minimal, nonsignificant effects on mean arterial and diastolic blood pressure and no effect on fetal heart rate, fetal arterial blood gas values, and maternal cardiovascular variables. The authors concluded that the fetal hypoxia observed in other animal studies, when nicardipine was administered to the mother, was not due to changes in umbilical or ductal blood flow but to a decrease in maternal uterine blood flow (15).

A single 10-mg dose of nicardipine was given to eight women with acute hypertension (diastolic blood pressure >105 mm Hg) in the 3rd trimester of pregnancy (16). A significant decrease in maternal diastolic, but not in systolic, pressure was observed during the next 60 minutes with an onset at 15 minutes.

Nicardipine has been used in human pregnancy for the treatment of hypertension (17,18). Forty women with mild or moderate hypertension (25 with gestational hypertension without proteinuria, 3 with preeclampsia, and 12 with chronic hypertension) were treated with oral nicardipine 20 mg 3 times a day, beginning at 28 weeks' gestation through the 7th postpartum day, a mean duration of 9 weeks (17). An additional 20 women were treated with IV nicardipine for severe preeclampsia, 5 of whom also had chronic hypertension, beginning at a mean 33 weeks' gestation (range 27–40 weeks). The IV dose used was based on body weight: 2 mg/hour (N=9; <80 kg), 4 mg/hour (N=8; 80–90 kg), and 6 mg/hour (N=3; >90 kg). The mean duration of IV therapy was 5.3 days (range 2–15 days). Low placental passage of nicardipine was demonstrated in 10 women, 7 on oral therapy and 3 receiving IV therapy, but no accumulation of the drug was observed in the fetus. No perinatal deaths, fetal adverse effects, or adverse neonatal outcomes attributable to nicardipine were observed during treatment. Both umbilical and cerebral Doppler velocimetry remained stable throughout the study (17).

A study published in 1994 compared nicardipine and metoprolol in the treatment of hypertension (pregnancy-induced, preeclampsia, and chronic) during pregnancy (18). Fifty patients were treated in each group starting at a gestational age of about 29 weeks. Nicardipine decreased maternal systolic and diastolic blood pressure and umbilical artery resistance significantly more than metoprolol and significantly fewer patients required a cesarean section for fetal distress (6% vs. 28%). The difference in birth weights in the two groups was 201 g (2952 vs. 2751 g) (n.s.) (18).

A prospective multicenter cohort study of 78 women (81 outcomes; 3 sets of twins) who had 1st-trimester exposure to calcium channel blockers (none of whom took nicardipine) was reported in 1996 (19). Compared with controls, no increased risk of congenital malformations was found.

Breast Feeding Summary

The manufacturer states that significant amounts of nicardipine appear in milk of lactating rats (1). No reports on the use of nicardipine during nursing in humans or reports measuring the amount excreted into human milk have been located.

References

1. Product information. Cardene. Wyeth-Ayerst Pharmaceuticals, 2000.
2. Sejima Y, Sado T. Teratological study of 2-(N-benzyl-N-methylamino) ethyl methyl 2,6-dimethyl-4-m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (YC-93) in rats. Kiso to Rinsho 1979;13:1149–59. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:447.
3. Sato T, Nagaoka T, Fuchigami K, Ohsuga F, Hatano M. Reproductive studies of 2-(N-benzyl-N-methylamino) ethyl methyl 2,6-dimethyl-4-m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (YC-93) in rats and rabbits. Kiso to Rinsho 1979;13:1160–76. As cited in Shepard TH. Catalog of Teratogenic Agents. 6th ed. Baltimore, MD: Johns Hopkins University Press, 1989:447.
4. Parisi VM, Salinas J, Stockmar EJ. Fetal vascular responses to maternal nicardipine administration in the hypertensive ewe. Am J Obstet Gynecol 1989;161:1035–9.
5. Parisi VM, Salinas J, Stockmar EJ. Placental vascular responses to nicardipine in the hypertensive ewe. Am J Obstet Gynecol 1989;161:1039–43.
6. Csapo AI, Puri CP, Tarro S, Henzel MR. Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine. Am J Obstet Gynecol 1982;142:483–91.
7. Maigaard S, Forman A, Andersson KE, Ulmsten U. Comparison of the effects of nicardipine and nifedipine on isolated human myometrium. Gynecol Obstet Invest 1983;16:354–66.
8. Lirette M, Holbrook RH, Katz M. Effect of nicardipine HCl on prematurely induced uterine activity in the pregnant rabbit. Obstet Gynecol 1985;65:31–6.
9. Litette M, Holbrook RH, Katz M. Cardiovascular and uterine blood flow changes during nicardipine HCl tocolysis in the rabbit. Obstet Gynecol 1987;69:79–82.
10. Holbrook RH Jr, Lirette M, Katz M. Cardiovascular and tocolytic effects of nicardipine HCl in the pregnant rabbit: comparison with ritodrine HCl. Obstet Gynecol 1987;69:83–7.
11. Ducsay CA, Thompson JS, Wu AT, Novy MJ. Effects of calcium entry blocker (nicardipine) tocolysis in rhesus macaques: fetal plasma concentrations and cardiorespiratory changes. Am J Obstet Gynecol 1987;157:1482–6.
12. Jannet D, Abankwa A, Guyard B, Carbonne B, Marpeau L, Milliez J. Nicardipine versus salbutamol in the treatment of premature labor. A prospective randomized study. Eur J Obstet Gynaecol Reprod Med 1997;73:11–6.
13. Ross EL, Ross BS, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor (abstract). Am J Obstet Gynecol 1998;178:S181.
14. Larmon JE, Ross BS, May WL, Dickerson GA, Fischer RG, Morrison JC. Oral nicardipine versus intravenous magnesium sulfate for the treatment of preterm labor. Am J Obstet Gynecol 1999;181:1432–7.
15. Holbrook RH, Voss EM, Gibson RN. Ovine fetal cardiorespiratory response to nicardipine. Am J Obstet Gynecol 1989;161:718–21.
16. Walker JJ, Mathers A, Bjornsson S, Cameron AD, Fairlie FM. The effect of acute and chronic antihypertensive therapy on maternal and fetoplacental Doppler velocimetry. Eur J Obstet Gynecol Reprod Biol 1992;43:193–9.
17. Carbonne B, Jannet D, Touboul C, Khelifati Y, Milliez J. Nicardipine treatment of hypertension during pregnancy. Obstet Gynecol 1993;81:908–14.
18. Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipine versus metoprolol in the treatment of hypertension during pregnancy: a randomized comparative trial. Obstet Gynecol 1994;84:354–9.
19. 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.