al to the human exposure atthe MRHD (250 mg every 6 hours for a daily dose of 1000 mg) and an increased percent litter incidenceof total skeletal malformations at a plasma exposure approximately 6 times the human exposure at theMRHD. Reproductive studies with relebactam administered parenterally to pregnant rats and rabbitsduring the period of organogenesis at plasma exposures up to 7 and 24 times, respectively, the plasmaexposure in humans at the MRHD showed no adverse effects on pregnancy or embryofetal development.
Relebactam administered to rats during gestation through lactation was not associated with fetal toxicity,developmental delays, or impaired reproduction in first generation offspring at plasma exposuresequivalent to 8 times the human exposure at the MRHD (see Data).
The background risk of major birth defects and miscarriage for the indicated populations is unknown. Allpregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimatedbackground risk of major birth defects is 2 to 4 % and miscarriage is 15 to 20 % of clinically recognizedpregnancies within the U.S. general population.
Data
Animal Data
Imipenem and Cilastatin
Reproductive toxicity studies with imipenem and cilastatin (alone or in combination) administeredparenterally to mice, rats, and rabbits showed no evidence of effects on embryofetal (mice, rats, andrabbits) or pre/postnatal (rats) development. In embryofetal development studies, imipenem wasadministered intravenously to rats (gestation days (GD) 7 to 17), and rabbits (GD 6 to 18), at doses up to900 and 60 mg/kg/day, respectively, approximately 4 and 0.6 times the MRHD (based on body surfacearea comparison). Cilastatin was administered subcutaneously to rats (GD 6 to 17) and intravenously torabbits (GD 6 to 18) at doses up to 1000 and 300 mg/kg/day, respectively, approximately 5 and 3 timesthe MRHD (based on body surface area comparison). Imipenem/cilastatin was administered intravenouslyto mice at doses up to 320 mg/kg/day (GD 6 to 15) which is approximately equivalent to the MRHD basedon body surface area comparison, and to rats at intravenous doses up to 80 mg/kg/day and asubcutaneous dose of 320 mg/kg/day (GD 6 to 17). In a separate pre-postnatal development study, ratswere administered subcutaneous imipenem/cilastatin at doses up to 320 mg/kg/day (GD 15 to day 21postpartum). The subcutaneous dose of 320 mg/kg/day in rats is approximately double the MRHD basedon body surface area comparison.
Imipenem/cilastatin administered intravenously to pregnant cynomolgus monkeys during organogenesis(GD 21 to 50) at 100 mg/kg/day, a dose approximately equivalent to the MRHD (based on body surfacearea comparison), at an infusion rate mimicking human clinical use was not associated with fetalmalformations, but there was an increase in embryonic loss relative to controls. Imipenem/cilastatinadministered to pregnant cynomolgus monkeys during organogenesis at 40 mg/kg/day by bolusintravenous injection caused significant maternal toxicity including death and embryofetal loss.
Relebactam
In an embryofetal development study in pregnant mice, relebactam administered subcutaneously indoses of 80, 200, and 450 mg/kg/day during the period of organogenesis (GD 6 to 17) was not associatedwith maternal toxicity at doses up to 450 mg/kg/day. However, although individual skeletal malformationsappeared only as single occurrences in the high dose group, the percent litter incidence of to |
