Risk Summary

Available data regarding use of carvedilol phosphate extended-release capsules in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy. The use of beta-blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate (see Clinical Considerations). In animal reproduction studies, there was no evidence of adverse developmental outcomes at clinically relevant doses (see Data). Oral administration of carvedilol to pregnant rats during organogenesis resulted in post-implantation loss, decreased fetal body weight, and an increased frequency of delayed fetal skeletal development at maternally toxic doses that were 50 times the maximum recommended human dose (MRHD). In addition, oral administration of carvedilol to pregnant rabbits during organogenesis resulted in increased post-implantation loss at doses 25 times the MRHD (see Data). 

The estimated background risk of major birth defects and miscarriage for the indicated populations 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% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. 

Fetal/Neonatal Adverse Reactions: Neonates of women with hypertension who are treated with beta-blockers during the third trimester of pregnancy may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia, and respiratory depression and manage accordingly. 

Data

Animal Data: Studies performed in rats and rabbits given carvedilol during fetal organogenesis revealed increased post-implantation loss in rats at a maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m 2) and in rabbits (in the absence of maternal toxicity) at doses of 75 mg/kg/day (25 times the MRHD as mg/m 2). In the rats, there was also a decrease in fetal body weight at 300 mg/kg/day (50 times the MRHD as mg/m 2) accompanied by an increased incidence of fetuses with delayed skeletal development. In rats, the no-effect level for embryo-fetal toxicity was 60 mg/kg/day (10 times the MRHD as mg/m 2); in rabbits, it was 15 mg/kg/day (5 times the MRHD as mg/m 2). In a pre- and post-natal development study in rats administered carvedilol from late gestation through lactation, increased embryo-lethality was observed at a maternally toxic dose of 200 mg/kg/day (approximately 32 times the MRHD as mg/m 2), and pup mortality and delays in physical growth/development were observed at 60 mg/kg/day (10 times the MRHD as mg/m 2) in the absence of maternal toxicity. The no-effect level was 12 mg/kg/day (2 times the MRHD as mg/m 2). Carvedilol was present in fetal rat tissue.