8.1Pregnancy Risk Summary
There are no available data on the use of cocaine hydrochloride in pregnant women to identify a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Adverse maternal and fetal/neonatal outcomes have been seen in women with chronic cocaine abuse during pregnancy ( see Data ). In published animal reproduction studies, cocaine administered to pregnant females during the gestational period produced hydronephrosis (0.5 times the human reference dose (HRD) of 37.5 mg via the 4% solution), developmental delays in the offspring (1.5 times the HRD), cerebral hemorrhage and fetal edema (2.0 times the HRD), reduced fetal body weights and brain weights (2.6 times the HRD), and reduced fetal survival (3.7 times the HRD).
Single dose administration of cocaine intravenously during organogenesis in mice produced cryptochidism, anophthalmia, exencephaly, and delayed ossification at 7.8 times the HRD. In rats, a single dose of cocaine administered by intraperitoneal injection produced edematous fetuses, hemorrhages and limb defects at 12.9 times the HRD ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Human Data There are no available data on the use of intranasal cocaine hydrochloride solution in pregnant women to inform a drug-associated risk for major congenital malformations or miscarriage.
There are published data describing adverse developmental outcomes in women with chronic cocaine abuse during pregnancy. The published case-control and observational studies examining the effect of in utero cocaine exposure on fetal growth parameters, after controlling for confounding variables, found exposure was associated with reduced fetal growth compared with non-drug-abuse populations. Published data from a large number of studies of women with chronic cocaine abuse during pregnancy are inconsistent in their findings with regard to congenital malformations, prematurity, miscarriage, premature rupture of membranes and gestational hypertension.
The applicability of the findings from these studies of chronic abuse in pregnancy to a single topical exposure is limited. Animal Data Formal animal reproduction and development studies have not been conducted with intranasal cocaine hydrochloride. However, reproduction and development studies with cocaine have been reported in the published literature. Exposure margins below are based on body surface area comparison to the human reference dose (HRD) of 37.5 mg (estimated amount absorbed from the 160 mg (4%) cocaine-soaked pledgets).
Hydronephrosis was noted in embryos from pregnant rats treated wtih cocaine 2.1 mg/kg (0.5 times the HRD) and higher from Gestation Day 0 to 9. Cerebral hemorrhage and endematous fetuses were noted at 2.2 times the HRD and above). Developmental delays and altered spontaneous exploratory behavior in response to cocaine were reported in rat pups born to dams treated intravenously with 6 mg/kg cocaine (1.5 times the HRD) from Gestation Day 8 to 20 in the absence of maternal toxicity.
Reduced fetal body and brain weights and alterations in fetal central neurotransmitter levels were noted following treatment of pregnant mice with 20 mg/kg cocaine from gestation days 8 to 12 or 12 to 18 (2.6 times the HRD). Reduced fetal survival was noted when pregnant nonhuman primates were dosed with 0.3 mg/kg/h cocaine (3.7 times the HRD on per day basis) via a subcutaneous minipump from Gestation Day 24 to birth.
Exencephaly, cryptochidism, hydronephrosis, anophthalmia, delayed ossification, limb anomalies, and cerebral and intra-abdominal hemorrhage were reported following a single subcutaneous injection of 60 mg/kg cocaine (7.8 times the HRD) to pregant mice between Gestation Day 7 to 12. No significant maternal toxicity was reported at this dose. Deficits in associational learning were reported when pregnant rats were treated with cocaine during gestation (10.3 times the HRD) in the absence of maternal toxicity.
Hemorrhage, fetal edema, and limb defects were reported when pregnant rats were administered a single injection of cocaine at a dose of 50 mg/kg/day or higher (12.9 times the HRD) during Gestation Day 9 to 19. Increased resorptions were noted at doses higher than 70 mg/kg/day (18.1 times the HRD) when administered on Gestation Day 16. No adverse effects were reported at a dose of 40 mg/kg (10.3 times the HRD). Fetal deaths, decreased fetal body weights, edematous fetuses and single incidences of cleft palate and hypertrophic ventricle were observed when pregnant rats were treated with intraperitoneal cocaine at 60 mg/kg (15.5 times the HRD) from Gestation Day 8 to 12.
Maternal toxicity was noted at this dose (mortality). No adverse effect level for fetal and maternal toxicity was noted at 50 mg/kg/day (13 times the HRD). Decreased body weights, overall body length and crown circumference of offspring were reported when pregnant Rhesus monkeys were treated with escalating doses up to 7.5 mg/kg cocaine TID intramuscularly per day for 5 days per week from prior to conception to term (11.6 times the HRD).
