MEMANTINE HYDROCHLORIDE (Page 4 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

There was no evidence of carcinogenicity in a 113-week oral study in mice at doses up to 40 mg/kg/day (7 times the maximum recommended human dose [MRHD] on a mg/m2 basis). There was also no evidence of carcinogenicity in rats orally dosed at up to 40 mg/kg/day for 71 weeks followed by 20 mg/kg/day (14 and 7 times the MRHD on a mg/m2 basis, respectively) through 128 weeks.

Mutagenesis

Memantine produced no evidence of genotoxic potential when evaluated 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.

Impairment of Fertility

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 and/or Pharmacology

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 acute and repeat-dose neurotoxicity studies in female rats, oral administration of memantine and donepezil in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma memantine and donepezil exposures.

The relevance of these findings to humans is unknown.

14 CLINICAL STUDIES

The effectiveness of memantine hydrochloride extended-release capsules 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 Memantine Hydrochloride Extended-Release 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 ≥ 3 and ≤ 14 at Screening and Baseline) receiving acetylcholinesterase inhibitor (AChEI) therapy at a stable dose for 3 months prior to screening. The mean age of patients participating in this trial was 76.5 years with a range of 49 to 97 years. Approximately 72% of patients were female and 94% were Caucasian.

Study Outcome Measures

The effectiveness of memantine hydrochloride extended-release capsules was evaluated in this study using the co-primary efficacy parameters of Severe Impairment Battery (SIB) and the Clinician’s Interview-Based Impression of Change (CIBIC-Plus).

The ability of memantine hydrochloride extended-release capsules to improve cognitive performance was assessed with the Severe Impairment Battery (SIB), a multi-item instrument that has been validated for the evaluation of cognitive function in patients with moderate to severe dementia. The SIB examines selected aspects of cognitive performance, including elements of attention, orientation, language, memory, visuospatial ability, construction, praxis, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.

The ability of memantine hydrochloride extended-release capsules to produce an overall clinical effect was assessed using a Clinician’s Interview Based Impression of Change that required the use of caregiver information, the CIBIC-Plus. The CIBIC-Plus is not a single instrument and is not a standardized instrument like the ADCS-ADL or SIB. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-Plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-Plus evaluations from other clinical trials. The CIBIC-Plus used in this trial was a structured instrument based on a comprehensive evaluation at baseline and subsequent time-points of four domains: general (overall clinical status), functional (including activities of daily living), cognitive, and behavioral. It represents the assessment of a skilled clinician using validated scales based on his/her observation during an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-Plus is scored as a seven point categorical rating, ranging from a score of 1, indicating “marked improvement” to a score of 4, indicating “no change” to a score of 7, indicating “marked worsening.” The CIBIC-Plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.

Study Results

In this study, 677 patients were randomized to one of the following 2 treatments: memantine hydrochloride extended-release capsules 28 mg/day or placebo while still receiving an AChEI (either donepezil, galantamine, or rivastigmine).

Effects on Severe Impairment Battery (SIB)

Figure 1 shows the time course for the change from baseline in SIB score for the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the SIB change scores for the memantine hydrochloride extended-release capsules 28 mg/AChEI-treated (combination therapy) patients compared to the patients on placebo/AChEI (monotherapy) was 2.6 units. Using an LOCF analysis, memantine hydrochloride extended-release capsules 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

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Figure 1: Time course of the change from baseline in SIB score for patients completing 24 weeks of treatment

Figure 2 shows the cumulative percentages of patients from each treatment group who had attained at least the measure of improvement in SIB score shown on the X axis. The curves show that both patients assigned to memantine hydrochloride extended-release capsules 28 mg/AChEI and placebo/AChEI have a wide range of responses, but that the memantine hydrochloride extended-release capsules 28 mg/AChEI group is more likely to show an improvement or a smaller decline.

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Figure 2: Cumulative percentage of patients completing 24 weeks of double-blind treatment with specified changes from baseline in SIB scores

Figure 3 shows the time course for the CIBIC-Plus score for patients in the two treatment groups completing the 24 weeks of the study. At 24 weeks of treatment, the mean difference in the CIBIC-Plus scores for the memantine hydrochloride extended-release capsules 28 mg/AChEI-treated patients compared to the patients on placebo/AChEI was 0.3 units. Using an LOCF analysis, memantine hydrochloride extended-release capsules 28 mg/AChEI treatment was statistically significantly superior to placebo/AChEI.

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Figure 3: Time course of the CIBIC-Plus score for patients completing 24 weeks of treatment

Figure 4 is a histogram of the percentage distribution of CIBIC-Plus scores attained by patients assigned to each of the treatment groups who completed 24 weeks of treatment.

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Figure 4: Distribution of CIBIC-Plus ratings at week 24

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