Risk Summary

Limited published data on tetracaine use in pregnant women are not sufficient to inform any risks. Published epidemiologic studies of nasal oxymetazoline used as a decongestant during pregnancy do not identify a consistent association with any specific malformation or pattern of malformations [see Data] . In animal reproduction and development studies, oxymetazoline given subcutaneously to rats during the period of organogenesis caused structural abnormalities at a dose approximately 7.6 times the exposure of oxymetazoline HCl at the 0.3 mg maximum recommended human dose (MRHD) of KOVANAZE. In a pre- and post-natal development study, oxymetazoline given subcutaneously to rats caused embryo-fetal toxicity manifested by reduced implantation sites and live litter sizes at approximately 1.5 times the MRHD and increased pup mortality at 6 times the MRHD. No adverse developmental effects were observed following subcutaneous administration of tetracaine HCl only to rats and rabbits during organogenesis at 32 and 6 times, respectively, the estimated exposure of tetracaine HCl at the 18 mg MRHD of KOVANAZE [see Data] . 

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 and to 20%, respectively. 

Data

Human Data

Published epidemiologic studies of nasal oxymetazoline used as a decongestant during pregnancy do not identify a consistent association with any specific malformation or pattern of malformations. These data are limited by the small number of cases exposed, multiple comparisons which may have resulted in chance findings, and analyses based on decongestants as a group. 

Animal Data

In an embryo-fetal development study, pregnant rats were administered subcutaneous doses of oxymetazoline HCl only at 0.1 mg/kg, tetracaine HCl only at 7.5 mg/kg, or oxymetazoline HCl at 0.01, 0.03, and 0.1 mg/kg/day in combination with 7.5 mg/kg tetracaine HCl during the period of organogenesis (Gestational Days [GD] 7-17). Oxymetazoline HCl treatment at 0.1 mg/kg/day (7.6 times the oxymetazoline AUC exposure at the maximum recommended human dose [MRHD] of KOVANAZE [3 mg oxymetazoline HCl and 18 mg tetracaine HCl]) caused reduced fetal weight and structural abnormalities including external and skeletal malformations (e.g., short forelimb digits, fused arches in thoracic vertebrae, fused ribs, and irregular number of ribs), and variations (e.g., irregularly shaped arches and increased bifid centra in thoracic vertebrae, and un-ossified forelimb phalanx) in the presence of maternal toxicity (reduced food consumption, body weight gain, and absolute body weight); however, the structural abnormality findings cannot be clearly attributed to the maternal toxicity. Adverse developmental effects were not observed when pregnant rats were co-administered the same dose of oxymetazoline HCl in combination with 7.5 mg/kg/day tetracaine HCl, or with 7.5 mg/kg/day tetracaine HCl alone. The no-observed-adverse-effect-level (NOAEL) for fetal effects was 0.03 mg/kg/day oxymetazoline HCl (1.5 times the oxymetazoline AUC exposure at the MRHD) and 7.5 mg/kg/day tetracaine HCl (30 times the AUC exposure as measured by PBBA [major tetracaine metabolite] at the MRHD). 

In other embryo-fetal development studies, tetracaine base alone administered subcutaneously did not cause structural abnormalities in rats at doses up to 10 mg/kg/day (approximately 6.1 times the MRHD level of 18 mg tetracaine HCl by body surface area (BSA) comparison) or in rabbits at subcutaneous doses up to 5 mg/kg/day (approximately 6.1 times the MRHD level by BSA comparison). 

In a prenatal and postnatal development study, pregnant rats were given subcutaneous doses of oxymetazoline HCl only at 0.1 mg/kg/day, tetracaine HCl only at 7.5 mg/kg/day, and oxymetazoline HCl at 0.01, 0.03, and 0.1 mg/kg/day in combination with 7.5 mg/kg/day tetracaine HCl from GD 7 to Lactation Day [LD] 20 (corresponding to the beginning of organogenesis through parturition and subsequent pup weaning). Oxymetazoline HCl treatment decreased the mean number of implant sites/litter at ≥ 0.03 mg/kg (≥ 1.5 times the oxymetazoline AUC exposure at the MRHD) when administered with 7.5 mg/kg tetracaine HCl (approximately 9%) and without tetracaine HCl (5.5%), which resulted in a reduction in live litter sizes in these groups. At the end of the lactation period, fetal body weights were significantly decreased at 0.1 mg/kg oxymetazoline HCl (6 times the oxymetazoline AUC exposure at the MRHD) when administered alone (19%) and co-administered with 7.5 mg/kg/day tetracaine HCl (11%). In addition, a decrease in pup survival was observed at the 0.1/7.5 mg/kg oxymetazoline HCl/tetracaine HCl dose (91.9%) compared to the control (99.6%), but no effects in any other groups. Maternal toxicity (e.g., mortality and reduced body weight gain, absolute body weight and food consumption) occurred in groups administered 0.1 mg/kg/day oxymetazoline HCl; however, the adverse developmental findings observed at this dose cannot clearly be attributed to the maternal toxicity. There were no adverse effects on sexual maturation, neurobehavioral, or reproductive function in the offspring at any maternal dose. The no-effect level for oxymetazoline HCl for maternal reproduction was 0.01 mg/kg/day (0.5 times oxymetazoline AUC exposure at the MRHD) and for pup growth and development was 0.03 mg/kg/day (1.5 times oxymetazoline AUC exposure at the MRHD). The no-effect level for tetracaine HCl for maternal reproduction and pup growth and development was 7.5 mg/kg/day (12 times the AUC exposure as measured by PBBA at the MRHD).