gnancy have not shown an increased risk of major malformations. Based on these studies the incidence of neonatal abstinence syndrome is not clear and there does not appear to be a dose-response relationship.
Animal Data
BUNAVAIL has been shown to have differences in bioavailability compared to buprenorphine/naloxone-containing sublingual products. The exposure margins listed below are based on body surface area comparisons (mg/m2) to the recommended human sublingual dose of 16 mg buprenorphine from Suboxone, which is equivalent to the recommended human buccal dose (RHD) of 8.4 mg buprenorphine from BUNAVAIL.
Effects on embryo-fetal development were studied in Sprague-Dawley rats and Russian white rabbits following oral (1:1) and intramuscular (IM) (3:2) administration of mixtures of buprenorphine and naloxone. Following oral administration to rats and rabbits, no teratogenic effects were observed at buprenorphine doses up to 250 mg/kg/day and 40 mg/kg/day, respectively (estimated exposure approximately 150 times and 50 times, respectively, the RHD). No definitive drug-related teratogenic effects were observed in rats and rabbits at IM doses up to 30 mg/kg/day (estimated exposure approximately 20 times and 35 times, respectively, the RHD). Acephalus was observed in one rabbit fetus from the low-dose group and omphalocele was observed in two rabbit fetuses from the same litter in the mid-dose group; no findings were observed in fetuses from the high-dose group. Following oral administration of buprenorphine to rats, dose-related post-implantation losses, evidenced by increases in the numbers of early resorptions with consequent reductions in the numbers of fetuses, were observed at doses of 10 mg/kg/day or greater (estimated exposure approximately 6 times the RHD). In the rabbit, increased post implantation losses occurred at an oral dose of 40 mg/kg/day. Following IM administration in the rat and the rabbit, post-implantation losses, as evidenced by decreases in live fetuses and increases in resorptions, occurred at 30 mg/kg/day.
Buprenorphine was not teratogenic in rats or rabbits after IM or subcutaneous (SC) doses up to 5 mg/kg/day (estimated exposure was approximately 3 and 6 times, respectively, the RHD), after IV doses up to 0.8 mg/kg/day (estimated exposure was approximately 0.5 times and equal to, respectively, the RHD), or after oral doses up to 160 mg/kg/day in rats (estimated exposure was approximately 95 times the RHD) and 25 mg/kg/day in rabbits (estimated exposure was approximately 30 times the RHD). Significant increases in skeletal abnormalities (e.g., extra thoracic vertebra or thoraco-lumbar ribs) were noted in rats after SC administration of 1 mg/kg/day and up (estimated exposure was approximately 0.6 times the RHD), but were not observed at oral doses up to 160 mg/kg/day. Increases in skeletal abnormalities in rabbits after IM administration of 5 mg/kg/day (estimated exposure was approximately 6 times the RHD) or oral administration of 1 mg/kg/day or greater (estimated exposure was approximately equal to the RHD) were not statistically significant.
In rabbits, buprenorphine produced statistically significant pre-implantation losses at oral doses of 1 mg/kg/day or greater and post-implantation losses that were statistically significant at IV doses of 0.2 mg/kg/day or greater (estimated exposure approximately 0.3 times the RHD).
Dystocia was noted in pregnant rats treated intramuscularly with buprenorphine 5 mg/kg |
