8.1Pregnancy Risk Summary
This formulation of Vancomycin Injection is not recommended for use during the first or second trimester of pregnancy because it contains the excipients, PEG 400 and NADA, which caused fetal malformations in animal reproduction studies (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 and NADA.
The available data on use of this formulation of Vancomycin Injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available published data on vancomycin (without the excipients PEG 400 and NADA) use 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. 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 based on body surface area (see Data ) . Reproduction studies in rabbits with intravenous doses of PEG 400 at approximately 8 times the maximum daily human dose based on systemic exposures of PEG 400 during organogenesis resulted in fetal spinal malformations.
Reproduction studies in rabbits and rats using intravenous doses of NADA at approximately 32 and 20 times the maximum daily human dose, respectively, based on systemic exposures of NADA resulted in maternal toxicity and fetal spinal and cardiovascular malformations in rabbits, and maternal toxicity with no adverse embryo-fetal effects in rats. 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 based on body surface area (see Data ) .
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 Available data from postmarketing cases on use of this formulation of vancomycin injection (with the excipients PEG 400 and NADA) in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or infant outcomes.
There are no available data on first trimester use of vancomycin (without the excipients PEG 400 and NADA); however, available published data on use in pregnancy during the second and third trimesters have not shown an association with adverse pregnancy related outcomes. A published study evaluated hearing loss and nephrotoxicity in infants of 10 pregnant intravenous drug users treated with 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 (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 rabbits.
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). Animal reproduction studies conducted in rabbits administered intravenous PEG 400 at 2000 mg/kg (approximately 8 times the maximum daily human dose, based on AUC levels of PEG 400) 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.
No maternal toxicity was observed up to the maximum dose tested. Similarly, in animal reproduction studies conducted in pregnant rabbits (gestation days 6 to 19) and pregnant rats (gestation days 6 to 17) administered intravenous NADA at 1680 and 3780 mg/kg, respectively (at 32 times or greater based on AUC levels of NADA) resulted in fetal scoliosis and a spectrum of cardiovascular anomalies in rabbits 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 (12.3) ] . 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).
