Memantine produced no evidence of genotoxic potential when eva luated in the in vitro S. typhimurium or E. coli reverse mutation assay, an in vitro chromosomal aberration test in human lymphocytes, an in vivo cytogenetics assay for chromosome damage in rats, and the in vivo mouse micronucleus assay. The results were equivocal in an in vitro gene mutation assay using Chinese hamster V79 cells.

No impairment of fertility or reproductive performance was seen in rats administered up to 18 mg/kg/day (6 times the MRHD on a mg/m2 basis) orally from 14 days prior to mating through gestation and lactation in females, or for 60 days prior to mating in males.

13.2 Animal Toxicology Memantine induced neuronal lesions (vacuolation and necrosis) in the multipolar and pyramidal cells in cortical layers III and IV of the posterior cingulate and retrosplenial neocortices in rats, similar to those which are known to occur in rodents administered other NMDA receptor antagonists. Lesions were seen after a single dose of memantine. In a study in which rats were given daily oral doses of memantine for 14 days, the no-effect dose for neuronal necrosis was 4 times the maximum recommended human dose (MRHD of 28 mg/day) on a mg/m2 basis.

In a neurotoxicity study, female rats were given oral doses of memantine (3, 10, 30, 60 mg/kg/day) alone or in combination with donepezil (3, 10 mg/kg/day) for 28 days. When administered alone, memantine induced neurodegeneration only at 60 mg/kg/day; however, when administered in combination with 10 mg/kg/day donepezil, memantine induced neurodegeneration at doses of 30 and 60 mg/kg/day. When 60 mg/kg/day memantine and 10 mg/kg/day donepezil were administered in combination, the incidence and severity of neurodegeneration was increased compared to that with 60 mg/kg/day memantine alone or with 30 mg/kg/day memantine in combination with 10 mg/kg/day donepezil. In addition, the combination of 60 mg/kg/day memantine and 10 mg/kg/day donepezil was associated with widespread neurodegeneration in cortical areas (perirhinal, temporal, entorhinal, frontal, insular, piriform) and in olfactory nucleus and subiculum, whereas in the other affected groups, there was limited cortical (entorhinal, retrosplenial) involvement. At the no-effect level of the combination (10 mg/kg/day memantine + 10 mg/kg/day donepezil), plasma exposures of memantine were similar to (AUC) or two times (Cmax) those expected in humans at the MRHD; plasma exposures of donepezil were 3 (AUC) or 6 (Cmax) times those in humans at the MRHD of donepezil (10 mg/day). In a published study, similar donepezil-mediated exacerbation of memantine-induced neurodegeneration was observed in female rats given single doses of memantine in combination with donepezil, both administered by intraperitoneal injection.

The potential for induction of central neurodegenerative lesions by NMDA receptor antagonists in humans is unknown.

14 CLINICAL STUDIES

The effectiveness of NAMENDA XR as a treatment for patients with moderate to severe Alzheimer's disease was based on the results of a double-blind, placebo-controlled trial.

24-week Study of NAMENDA XR Capsules

This was a randomized double-blind clinical investigation in outpatients with moderate to severe Alzheimer's disease (diagnosed by DSM-IV criteria and NINCDS-ADRDA criteria for AD with a Mini Mental State Examination (MMSE) score &g