tal skeletalmalformations (skull and vertebral) was increased in the high-dose group (21 % litter incidence)compared to the concurrent control value (5.3 % litter incidence). The plasma relebactam exposure forthe high dose associated with increased skeletal malformations was approximately 6 times greater thanthe human plasma exposure at the MRHD based on AUC comparison. Also, mice receiving the lowestadministered dose of relebactam, 80 mg/kg/day, exhibited a higher percent litter incidence (15 % litterincidence) of cleft palate (a rare malformation in mice) compared to the concurrent control value (0 % litterincidence) and historical control values (up to 11 % litter incidence). This finding did not increase in adose-dependent manner with percent litter incidences of 0 % and 5.3 % in the mid- and high-dose groupsrespectively. The plasma AUC exposure for the low dose of relebactam associated with increased cleft
palate was approximately equivalent to the human plasma AUC at the MRHD. In embryofetaldevelopment studies in rats and rabbits, intravenous relebactam was administered to rats in doses of 50,150, and 450 mg/kg/day and rabbits in doses of 35, 275, and 450 mg/kg/day. In these studies,relebactam administered during the period of organogenesis to pregnant rats (GD 6 to 20) and rabbits(GD 7 to 20) was not associated with maternal or embryofetal toxicity at doses up to 450 mg/kg/daycorresponding to plasma AUC exposures of approximately 7 and 24 times, respectively, the humanplasma AUC at the MRHD.
In a pre-postnatal development study, relebactam administered intravenously in doses of 65, 200, and450 mg/kg/day to rats from GD 6 to lactation day (LD) 20 produced no maternal toxicity and did not impairthe physical and behavioral development or reproduction in first generation offspring at doses up to450 mg/kg/day corresponding to a plasma AUC exposure of approximately 8 times the plasma AUCexposure in humans at the MRHD.
Studies in pregnant rats and rabbits showed that relebactam is transferred to the fetus through theplacenta, with fetal plasma concentrations up to 5 % to 6 % of maternal concentrations observed onGD 20.
8.2 Lactation
Risk Summary
There are insufficient data on the presence of imipenem/cilastatin and relebactam in human milk, and nodata on the effects on the breastfed child, or the effects on milk production. Relebactam is present in themilk of lactating rats (see Data).
The developmental and health benefits of breastfeeding should be considered along with the mother’sclinical need for RECARBRIO and any potential adverse effects on the breastfed child from RECARBRIOor from the underlying maternal condition.
Data
Relebactam administered intravenously to lactating rats at a dose of 450 mg/kg/day (GD 6 to LD 14), wasexcreted into the milk with concentrations of approximately 5 % that of maternal plasma concentrations.
8.4 Pediatric Use
The safety and efficacy of RECARBRIO in patients younger than 18 years of age have not been
established.
8.5 Geriatric Use
Of the 216 patients treated with imipenem/cilastatin plus relebactam 250 mg in Trials 1 and 2, 67 (31.0 %)were 65 years of age or older, including 25 (11.6 %) patients 75 years of age and older.RECARBRIO is known to be substantially excreted by the kidney, and the risk of adverse reactions to thisdrug may be greater in patients with impaired renal function. Because elderly patients are more likely tohave decreased renal function, care should be taken in dose selection, and it may be |
