Risk Summary

This formulation of Vancomycin Injection administered intravenously or orally is not recommended for use during the first or second trimester of pregnancy because it contains the excipient, PEG 400, which caused fetal malformations in animal reproduction studies following intravenous administration (see Data). Advise pregnant women of the potential risk to the fetus. If therapy with Vancomycin Injection is needed during the first or second trimester of pregnancy, use other available formulations of vancomycin free of PEG 400.

There are no available data on use of this formulation of Vancomycin Injection (with the excipient PEG 400) in pregnant women to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or infant outcomes. Available published data on use of vancomycin (without the excipient PEG 400) administered intravenously in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes (see Data). There are no available data on first trimester use of vancomycin in pregnant women to assess the risk of major birth defects or miscarriage. Systemic absorption of vancomycin is low following oral administration of vancomycin hydrochloride capsules; however, absorption may vary depending on various factors [see Clinical Pharmacology (12.3)].

A reproduction study in rabbits with intravenous doses of PEG 400 during organogenesis, at approximately 13 times the maximum daily human dose of vancomycin, resulted in fetal spinal malformations. Vancomycin alone did not show adverse developmental effects when administered intravenously to pregnant rats and rabbits during organogenesis at doses less than or equal to the recommended maximum human dose (see Data).

There were no oral embryo-fetal toxicity studies conducted in animals with this formulation of Vancomycin Injection. Based on the uncertainty with oral bioavailability of PEG 400, the potential adverse developmental effect of PEG 400 with oral administration is unknown.

The estimated background risk of major birth defects and miscarriage for the indicated population is 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.

Data

Human Data

There are no available data on first trimester use of vancomycin, including vancomycin with the excipients PEG 400 and N-acetyl D-alanine (NADA), in pregnant women to assess a risk of major birth defects or miscarriage.

A published study evaluated hearing loss and nephrotoxicity in infants of 10 pregnant intravenous drug users treated with intravenously administered vancomycin (formulation did not include the excipients PEG 400 and NADA) for suspected or documented methicillin-resistant Staphylococcus aureus in the second or third trimester. The comparison groups were 10 uninfected non-intravenous drug-dependent patients, and 10 uninfected intravenous drug-dependent patients who served as substance abuse controls. No infant in the vancomycin exposed group had abnormal sensorineural hearing at 3 months of age or nephrotoxicity.

A published prospective study assessed outcomes in 55 pregnant women with a positive Group B streptococcus (GBS) culture and a high-risk penicillin allergy with resistance to clindamycin or unknown sensitivity who were administered vancomycin intravenously (formulation did not include the excipients PEG 400 and NADA) at the time of delivery. Vancomycin dosing ranged from the standard 1 g intravenously every 12 hours to 20 mg/kg intravenous every 8 hours (maximum individual dose 2 g). No major adverse reactions were recorded either in the mothers or their newborns. None of the newborns had sensorineural hearing loss. Neonatal renal function was not examined, but all of the newborns were discharged in good condition.

Animal Data

Vancomycin did not cause fetal malformations when administered during organogenesis to pregnant rats (gestation days 6 to 15) and rabbits (gestation days 6 to 18) at the equivalent recommended maximum human dose (based on body surface area comparisons) of 200 mg/kg/day IV to rats or 120 mg/kg/day IV to rabbits1. No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (approximately 1 and 0.8 times the recommended maximum human dose based on body surface area, respectively). Maternal toxicity was observed in rats (at doses 120 mg/kg and above) and rabbits (at 80 mg/kg and above).

The excipient, PEG 400, administered intravenously to pregnant rabbits at 2000 mg/kg (approximately 13 times higher AUC levels of PEG 400 than in the maximum daily human dose of vancomycin) during organogenesis (gestation days 6 to 19) resulted in fetal scoliosis (thoracic and lumbar) and increased incidence of delayed or incomplete ossification of the pubes, epiphyses, and talus bones when compared with controls. No maternal toxicity was observed up to the maximum dose tested.

In animal reproduction studies conducted in pregnant rabbits (gestation days 6 to 19) and pregnant rats (gestation days 6 to 17) administered the excipient NADA intravenously at 1680 and 3780 mg/kg, respectively (approximately 96 times or more higher AUC levels of NADA than in the maximum daily human dose of vancomycin) resulted in fetal scoliosis and a spectrum of cardiovascular anomalies in rabbits when compared with controls and no adverse effects on fetuses in rats. Increased incidence of delayed or incomplete ossifications of the metacarpals/metatarsals/phalanges and increased ossification (fused jugal/maxilla bones) were observed in rabbits at 1680 mg/kg. Minor non adverse fetal skeletal abnormalities were observed in rats at 3780 mg/kg which was also associated with maternal toxicity including increased incidence of litter loss [see Clinical Pharmacology (12.6)].

There were no oral embryo-fetal toxicity studies conducted in animals with this Vancomycin Injection product. The oral bioavailability of PEG 400 in humans is uncertain. The oral bioavailability of NADA is unknown.

No animal studies have been conducted to evaluate the potential reproductive and embryo-fetal effects of Vancomycin Injection with the excipients PEG 400 and NADA.