Sedative/Anticonvulsant
PREGNANCY RECOMMENDATION: Human Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The effects of benzodiazepines on the human embryo and fetus are controversial. Although some studies have reported an association with various types of congenital defects, other studies have not found such associations (see also Chlordiazepoxide or Diazepam). Maternal denial of exposure and concurrent exposure to other toxic drugs and substances (e.g., alcohol and smoking) may be confounding factors. If the maternal condition requires use of the drug during pregnancy, the lowest possible dose should be taken.
FETAL RISK SUMMARY
Clorazepate is a member of the benzodiazepine class of agents. The drug undergoes rapid metabolism to an active metabolite, nordiazepam, so there is essentially no circulating parent drug. Plasma protein binding of nordiazepam and its elimination half-life is about 40–50 hours. No teratogenic effects were observed in rats and rabbits fed large doses of the drug during gestation (1). The pharmacokinetics of clorazepate have been determined in pregnant women (2,3).
Consistent with the molecular weight (about 409) of the parent drug, the active metabolite, nordiazepam, crosses the human placenta and has been measured in amniotic fluid at 13 to 40 weeks’ gestation, umbilical cord blood (both arterial and venous), and in milk (2).
One report described multiple anomalies in an infant exposed to clorazepate during the 1st trimester (4). Exposure may have commenced as early as the 3rd week of gestation (5th week after the last menstrual period). The woman reportedly consumed 23 doses of the drug during the 1st trimester. Deformities present in the infant at birth were distended abdomen, oval mass in the suprapubic area, skin tag at site of penis without a urethral opening, absent scrotum and anus, marked shortening of the right thigh, bifid distal part of left foot, left great toe abnormality, right foot with four toes and an abnormal great toe, short digit attached to right finger in place of the thumb on left hand, deformities of the sacrum and fourth and fifth lumbar vertebrae with a narrowed pelvis, underdeveloped right femur, absent right fibula, absence of two left metacarpal bones, hypoplasia of first right metacarpal bone, patent ductus arteriosus, absence of right lung lobe, cecum, rectum, and right kidney, and the presence of several supernumerary spleens. The infant died 24 hours after birth (4).
In an unconfirmed, retrospective report of oral contraceptive drug interactions, one woman became pregnant while taking a combination tablet of ethinyl estradiol 80 mcg/norethindrone 1 mg (5). The only other medications consumed immediately prior to the pregnancy were clorazepate and an unidentified cold tablet. The authors speculated that a possible interaction may have occurred between the antihistamine in the cold tablet and the contraceptive. Although the woman claimed she did not miss any doses of the oral contraceptive, there was no confirmation of compliance (5). Interpretation of this interaction, if it exists, is not possible.
The Lamotrigine Pregnancy Registry, an ongoing project conducted by the manufacturer, was first published in January 1997 (6). The final report was published in July 2010. The Registry is now closed. In two prospectively enrolled pregnancies exposed in the 1st trimester to clorazepate and lamotrigine, with or without other anticonvulsants, there was one fetal death and one spontaneous abortion (6).
BREASTFEEDING SUMMARY
No reports describing the use of clorazepate during human lactation have been located.
However, following a single 20-mg clorazepate dose administered IM to seven women during labor, low concentrations of nordiazepam, the active metabolite, were found in milk at 2 days postdose (average 10.0 ng/mL, range 7.5–15.5 ng/mL) and at 4 days (average 9.4 ng/mL, range 6–12 ng/mL). The milk:maternal blood ratios were 0.18 and 0.23, respectively. In infant blood at 2 days, only trace amounts were measured in five with 4 ng/mL and 7.5 ng/mL levels in the other two. In five infants at 4 days, the average concentration was 5.7 ng/mL (range 4–8.5 ng/mL). In the other two infants, one had trace amounts and the other had a coagulated sample. In absolute terms, the amounts were considered negligible (2).
Other benzodiazepines accumulate in human milk, and adverse effects in the nursing infant have been reported (see Diazepam). The American Academy of Pediatrics classifies other benzodiazepines as drugs whose effect on the nursing infant is unknown but may be of concern (e.g., see Diazepam).
References
1.Product information. Clorazepate Dipotassium. Mylan Pharmaceuticals, 2010.
2.Rey E, Giraux P, d’Athis PH, Turquais JM, Chavinie J, Olive G. Pharmacokinetics of the placental transfer and distribution of clorazepate and its metabolite nordiazepam in the feto-placental unit and in the neonate. Eur J Clin Pharmacol 1979;15:181–5.
3.Rey E, d’Athis PH, Giraux P, de Lauture D, Turquais JM, Chavinie J, Olive G. Pharmacokinetics of clorazepate in pregnant and non-pregnant women. Eur J Clin Pharmacol 1979;15:175–80.
4.Patel DA, Patel AR. Clorazepate and congenital malformations. JAMA 1980;244:135–6.
5.DeSano EA Jr, Hurley SC. Possible interactions of antihistamines and antibiotics with oral contraceptive effectiveness. Fertil Steril 1982;37:853–4.
6.The Lamotrigine Pregnancy Registry. Final Report. 1 September 1992 through 31 March 2010. GlaxcoSmithKline, July 2010.