A Review of Memantine (NAMENDA) for Alzheimer’s Disease

Memantine (NAMENDA) is the first drug approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe Alzheimer’s disease dementia. Other drugs approved for the treatment of Alzheimer’s are specifically approved only for mild to moderately severe dementia.

One theory is that Alzheimer’s disease may be caused, in part, by over activation of N-methyl-D-aspartate (NMDA) receptors by the brain transmitter glutamate, that may add to the destruction of nerve cells. Memantine is postulated to work by blocking the NMDA receptors from binding to glutamate, thereby preventing cell death.

Memantine is not a new drug. It has been marketed in Europe since the 1980s. Since 1982, it has been sold for the treatment of Parkinsonism, cerebral and peripheral spasticity, and organic brain syndrome in Germany under the brand name Akatinol. In 2002, the European Union approved memantine for the treatment of Alzheimer’s disease. The original drug application for U.S. approval was submitted in July 2002 and then resubmitted in December with an additional study. The FDA ultimately approved memantine in October 2003.

The chemical structure of memantine is nearly identical to that of amantadine (SYMMETREL) differing by only two carbon atoms. Amantadine is also an NMDA inhibitor, and is approved by the FDA for the prevention and treatment of influenza A, Parkinson’s disease, and drug-induced movement disorder.

In a French medical journal review of memantine, the editors of Prescrire International, a highly respected source of independent drug information, state that:

“... data on the effects of memantine in severe Alzheimer’s disease are sparse and weak.”

In the United Kingdom, the editors of the Drug and Therapeutics Bulletin, also a highly respected source of independent drug information, concluded their review of the drug by saying:

“On published evidence, memantine produces, at best, only a small reduction in the rate of deterioration in global, functional, and cognitive scales in such patients. Whether this translates into important changes in quality of life or how long the effects last is unclear.”

The FDA guidelines for approval of drugs to treat Alzheimer’s disease require that studies demonstrate a statistically significant effect on two primary outcome measures: (1) cognitive function; and (2) global patient functioning or activities of daily function. The FDA medical officer reviewing the data submitted by Forest Laboratories states:

“There was a small effect size [difference] between memantine treated and placebo treated groups on cognitive improvement.”

He continued to comment on the measures of global functioning:

“Only a small minority of patients treated with memantine showed even a minimal or moderate improvement, with no patients showing a marked improvement, and the most common response being no change.”

Furthermore, an analysis by the FDA statistician of a subgroup of patients showed memantine failed to demonstrate a significant effect on patient global function for severe dementia of the Alzheimer’s type.

Although memantine shows a modest effect on improvement compared with placebo for moderately severe Alzheimer’s disease, the effectiveness of memantine has not been compared with any of the acetylcholinesterase inhibitors.

The effect of memantine on the progression of the disease is summed up in the drug’s professional product labeling or package which states:

“At this time, there is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer’s disease.”

One highly-touted study purports to show that the use of memantine causes significant decrease in caregiver time needed to be spent with Alzheimer’s disease. Although this study allegedly randomized patients to get either memantine or a placebo, there were statistically significant differences between the patients who eventually got the placebo and those who eventually were given memantine before the study began. Thus, any conclusions about the positive effects of the drug are, at the least, highly suspect.

Common adverse effects reported with memantine include dizziness, headache, constipation, pain, and difficult breathing, which are believed to be related to the dose of the drug. Three reports of inflammation of the pancreas and four cases of renal failure were reported from ongoing trials. Of the renal failure reports, the treatment assignments remain blinded for three cases. From post-marketing surveillance, two cases of a severe skin reaction called epidermal necrolysis, one case of bone marrow failure to make blood cells, and one case of liver failure were reported.

Since memantine is already marketed in Germany, the company has received 73 adverse event reports for 48 patients including seizures, high blood pressure, circulatory failure, jerky movements, bullous rash, pruritis, nervousness, tremors, aggressive reactions, and nausea.