Calcium Channel Blocker
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Moderate Risk
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
Three reports, totaling five pregnancies, have described the use of amlodipine in human pregnancy. The outcomes of these pregnancies were two normal term-infants, one growth-restricted newborn (no relationship to drug because of timing of exposure), one fetal death (cause unknown, but possibly related to other exposures), and one neonate with a rare skin disease (doubtful relationship to drug).
FETAL RISK SUMMARY
Amlodipine is a calcium channel blocking agent used in the treatment of hypertension and angina. It is the same calcium channel blocker subclass as nine other agents (see Appendix). Amlodipine is extensively converted to inactive metabolites. Plasma protein binding is about 93% and the terminal elimination half-life is about 30–50 hours (1).
The drug is not teratogenic or embryotoxic in rats and rabbits given doses up to 8 and 23 times, respectively, the maximum recommended human dose based on BSA (MRHD) during organogenesis. However, rats administered 8 times the MRHD for 14 days before mating and throughout gestation had a significant decrease in litter size (by about 50%), a significant increase in intrauterine deaths (about fivefold), and prolonged labor and gestation. This dose, however, had no effect on fertility in the rat (1).
It is not known if amlodipine crosses the human placenta. The molecular weight (about 567 for the besylate salt) and the long terminal elimination half-life suggest that it will cross to the embryo–fetus.
A 1998 case report described an unusual condition in a neonate whose mother had been treated for hypertension with amlodipine throughout gestation (2). The 3.97-kg male infant had been born at 39 weeks’ with meconium staining of the amniotic fluid at Apgar scores of 3 and 8 at 1 and 5 minutes, respectively, and required oxygen therapy. At 24 hours of age, the infant developed firm, red, pea-sized nodular lesions over most of his body. The skin lesions were extremely tender requiring morphine analgesia. A skin biopsy revealed needle-like crystals within adipocytes of the SC fat. On the second day of life, he had two generalized tonic–clonic seizures. Although his general clinical condition improved over the 1st week of life with no further seizures, the skin changes, diagnosed as SC fat necrosis of the newborn, persisted until 9 months of age. The cause of the infant’s condition was unknown (2).
A 2007 report described three hypertensive women exposed to amlodipine in the 1st trimester (3). In the first case, the mother took amlodipine 5 mg/day until 7 weeks’ gestation and then declined further treatment. Her blood pressure remained in good control throughout gestation. At about 38 weeks, she delivered a healthy, 3750-g female infant with Apgar scores of 9 and 10 at 1 and 5 minutes, respectively. The infant was healthy at 3 months of age with normal development (see also Breastfeeding Summary). The second case involved treatment with amlodipine until about 2 weeks’ gestation at which time the therapy was changed to atenolol 50 mg/day. Just before the seventh week the woman declined further treatment. Her blood pressure remained in good control throughout pregnancy. The growth-restricted (2600 g; <10th percentile), but otherwise-normal female infant was born at about 39 weeks’ with Apgar scores of 8 and 9 at 1 and 5 minutes, respectively. At 20 months of age, the 10-kg child was still growth-restricted, and intellectual delay and weakness in the left arm and hand grasp were noted. The cause of the condition was unknown but not thought to be related to the drug therapy. The third case involved a woman with polycystic kidney disease and hypertension that was being treated with imidapril 5 mg/day (an ACE inhibitor) and barnidipine 10 mg/day (a calcium channel blocker) in an unknown pregnancy. Because of uncontrolled blood pressure, her therapy was changed at about 8 weeks’ to amlodipine 5 mg/day. The mother also was taking sucralfate for acute gastritis and lorazepam for anxiety, and reported occasional use of 1 ounce of alcohol. At 12 weeks’, an ultrasound revealed no cardiac activity and she underwent dilatation and evacuation of a dead fetus (3).
A 26-year-old woman with pulmonary arterial hypertension conceived while taking amlodipine (dose not specified) and warfarin (4). Warfarin was discontinued (exact gestational timing not specified) and replaced with enoxaparin. The patient remained on amlodipine and enoxaparin throughout pregnancy. At about 38 weeks’, a cesarean section was performed to deliver a 3123-g male infant with Apgar scores of 9 and 9. The infant went home with his mother, and no other information was provided on the infant (4).
BREASTFEEDING SUMMARY
The molecular weight (about 567 for the besylate salt) and the long terminal elimination half-life (30–50 hours) suggest that it will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. However, no adverse effects were reported in the case below.
A mother 2 weeks postpartum, who was exclusively breastfeeding her infant, was restarted on amlodipine 5 mg/day to control her hypertension (3). At 3 months of age, the healthy female infant weighed 6.3 kg (25th–50th percentile) and had normal physical and neurodevelopment.
Although not mentioning amlodipine, the American Academy of Pediatrics classifies nifedipine, another calcium channel blocker, as compatible with breastfeeding (5).
References
1.Product information. Norvasc. Pfizer, 2000.
2.Rosbotham JL, Johnson A, Haque KN, Holden CA. Painful subcutaneous fat necrosis of the newborn associated with intra-partum use of a calcium channel blocker. Clin Exp Dermatol 1998;23:19–21.
3.Ahn HK, Nava-Ocampo AA, Han JY, Choi JS, Chung JH, Yang JY, Koong MK, Park CT. Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding. Hypertens Pregnancy 2007;26:179–87.
4.Nahapetian A, Oudiz RJ. Serial hemodynamics and complications of pregnancy in severe pulmonary arterial hypertension. Cardiology 2008;109:237–40.
5.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.