Carcinogenesis
Gabapentin was given in the diet to mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000mg/kg/day are 10times higher than plasma concentrations in humans given 3600mg/day. The pancreatic acinar cell tumours in male rats are low‑grade malignancies, did not affect survival, did not metastasise or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is unclear.
Mutagenesis
Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
Impairment of Fertility
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).
Teratogenesis
Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25times respectively, the daily human dose of 3600mg, (four, five or eight times, respectively, the human daily dose on a mg/m2 basis).
Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000mg/kg/day during organogenesis and in rats given 500, 1000, or 2000mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5times the human dose of 3600mg on a mg/m2 basis.
No effects were observed in pregnant mice given 500mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).
An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000mg/kg/day in a fertility and general reproduction study, 1500mg/kg/day in a teratology study, and 500, 1000, and 2000mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5times the human dose of 3600mg on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of post‑implantation fetal loss, occurred in doses given 60, 300, and 1500mg/kg/day during organogenesis. These doses are approximately 1/4 to 8times the daily human dose of 3600mg on a mg/m2 basis.
Carcinogenesis
Gabapentin was given in the diet to mice at 200, 600, and 2000mg/kg/day and to rats at 250, 1000, and 2000mg/kg/day for two years. A statistically significant increase in the incidence of pancreatic acinar cell tumours was found only in male rats at the highest dose. Peak plasma drug concentrations in rats at 2000mg/kg/day are 10times higher than plasma concentrations in humans given 3600mg/day. The pancreatic acinar cell tumours in male rats are low‑grade malignancies, did not affect survival, did not metastasise or invade surrounding tissue, and were similar to those seen in concurrent controls. The relevance of these pancreatic acinar cell tumours in male rats to carcinogenic risk in humans is unclear.
Mutagenesis
Gabapentin demonstrated no genotoxic potential. It was not mutagenic in vitro in standard assays using bacterial or mammalian cells. Gabapentin did not induce structural chromosome aberrations in mammalian cells in vitro or in vivo, and did not induce micronucleus formation in the bone marrow of hamsters.
Impairment of Fertility
No adverse effects on fertility or reproduction were observed in rats at doses up to 2000mg/kg (approximately five times the maximum daily human dose on a mg/m2 of body surface area basis).
Teratogenesis
Gabapentin did not increase the incidence of malformations, compared to controls, in the offspring of mice, rats, or rabbits at doses up to 50, 30 and 25times respectively, the daily human dose of 3600mg, (four, five or eight times, respectively, the human daily dose on a mg/m2 basis).
Gabapentin induced delayed ossification in the skull, vertebrae, forelimbs, and hindlimbs in rodents, indicative of fetal growth retardation. These effects occurred when pregnant mice received oral doses of 1000 or 3000mg/kg/day during organogenesis and in rats given 500, 1000, or 2000mg/kg prior to and during mating and throughout gestation. These doses are approximately 1 to 5times the human dose of 3600mg on a mg/m2 basis.
No effects were observed in pregnant mice given 500mg/kg/day (approximately 1/2 of the daily human dose on a mg/m2 basis).
An increased incidence of hydroureter and/or hydronephrosis was observed in rats given 2000mg/kg/day in a fertility and general reproduction study, 1500mg/kg/day in a teratology study, and 500, 1000, and 2000mg/kg/day in a perinatal and postnatal study. The significance of these findings is unknown, but they have been associated with delayed development. These doses are also approximately 1 to 5times the human dose of 3600mg on a mg/m2 basis.
In a teratology study in rabbits, an increased incidence of post‑implantation fetal loss, occurred in doses given 60, 300, and 1500mg/kg/day during organogenesis. These doses are approximately 1/4 to 8times the daily human dose of 3600mg on a mg/m2 basis.