The available data on the use of this formulation of TYZAVAN (which includes the excipient 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 (see Data). Available data over several decades of vancomycin (without the excipient NADA) use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).
Vancomycin 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).
The 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.
Available data from postmarketing cases on use of this formulation of vancomycin injection (with the excipient 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 excipient 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 intravenously administered vancomycin (formulation did not include the excipient NADA) for suspected or documented methicillin-resistant Staphylococcus aureus (MRSA) in the second or third trimester. The comparison groups were 10 non-intravenous drug-dependent patients who received no treatment, and 10 untreated 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 excipient 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 doses less than or equal to the 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). 1
Animal reproduction studies conducted in pregnant rabbits (gestation days 6 to 19) administered intravenous NADA at 1680 mg/kg (32 times the maximum daily human dose or greater based on AUC levels of NADA) resulted in fetal scoliosis and a spectrum of cardiovascular malformations. Increased incidence of delayed or incomplete ossifications of the metacarpals/metatarsals/phalanges and increased ossification (fused jugal/maxilla bones) were also observed in rabbits at 1680 mg/kg without maternal toxicity. No adverse developmental outcomes were observed in rabbits administered intravenous NADA at 560 mg/kg (11 times the maximum daily human dose based on AUC levels of NADA). In reproduction studies in pregnant rats (gestation days 6 to 17) administered intravenous NADA at 3780 mg/kg (20 times the maximum daily human dose based on AUC levels of NADA) no fetal adverse effects were observed. Maternal toxicity, including increased incidence of litter loss, was observed in rats at 3780 mg/kg [see Clinical Pharmacology (12.3)].
No animal studies have been conducted to evaluate the potential reproductive and embryo-fetal effects of TYZAVAN (with the excipient NADA).