Extended-Release Memantine Appears Safe and Effective in Alzheimer's

Allison Gandey

October 02, 2008

October 2, 2008 (Salt Lake City, Utah) — New trial data suggest that a large 28-mg, once-daily dose of memantine (Namenda, Axura, Forest Pharmaceuticals) in an extended-release formulation may be an option for treating moderate to severe Alzheimer's disease.

Results of the multinational, randomized, double-blind, placebo-controlled trial were presented here at the American Neurological Association 133rd Annual Meeting.

"Extended-release memantine in combination with a cholinesterase inhibitor provides significant benefits on measures of cognition, global status, behavior, and verbal fluency," lead investigator George Grossberg, MD, from St. Louis University, in Missouri, concluded.

"We don't have the ability to halt the disease or revive dead neurons," Dr. Grossberg told Medscape Neurology & Neurosurgery. "What we can do is perhaps buy patients and families a little more quality time."

Memantine is an N-methyl-D-aspartate-receptor antagonist indicated for the treatment of moderate to severe Alzheimer's disease. Current US Food and Drug Administration (FDA)–approved dosing recommends that memantine be administered in 10-mg twice-daily immediate-release tablets or solution.

"Often there's a dose-response curve — meaning the higher the dose the person can tolerate, the more response you get," Dr. Grossberg said. "The question is if one increased the dose of memantine from the usual 20 mg a day by almost 50%, to 28 mg a day, would you see perhaps better efficacy?"

Doses of 30 mg and higher have been associated with an increasing incidence of adverse events. The objective of this new trial was to assess whether this would be the case with a new 28-mg extended-release option.

A total of 677 patients were randomized in the study. All patients first completed a 2-week single-blind period of placebo administration followed by a 24-week double-blind period of treatment with additional placebo or extended-release memantine.

The parallel-group trial found that patients treated with memantine and a cholinesterase inhibitor showed an improvement over patients treated with the cholinesterase inhibitor and placebo.

Efficacy Summary at Baseline and Week 24

Outcome Measure Treatment n Mean Baseline Mean End-Point Change From Baseline Least-Squares Mean Difference (95% CI) P
Severe impairment battery Memantine/ChEI* 332 76.8 2.7 2.6 (1.0 to 4.2) 0.001
  Placebo/ChEI 327 75.2 0.3    
Clinician's impression plus caregiver input Memantine/ChEI 333 NA 3.8 NA 0.008
  Placebo/ChEI 328 NA 4.1 NA  
19-item activities of daily living score Memantine/ChEI 331 33.1 -0.7 0.7 (-0.3 to 1.8) 0.177
  Placebo/ChEI 328 32.8 -1.3    
Neuropsychiatric inventory Memantine/ChEI 318 17.2 -4.3 -2.7 (-4.5 to -0.8) 0.005
  Placebo/ChEI 321 16.5 -1.6    
Verbal fluency Memantine/ChEI 330 5.8 0.3 0.5 (0.2 to 0.9) 0.004
  Placebo/ChEI 326 5.7 -0.3    

*ChEI = Cholinesterase inhibitor

Investigators report that extended-release memantine was well tolerated. In both groups, most adverse events were mild or moderate in severity. The most common adverse effects occurred in a higher percentage of memantine-treated patients than placebo.

Adverse Events

Event Memantine/ChEI

(n=273), %

Placebo/ChEI

(n=272), %

Headache 5.6 5.1
Diarrhea 5.0 3.9
Dizziness 4.7 1.5

size="1">*ChEI = Cholinesterase inhibitor

A total of 4 memantine-treated and 5 placebo-treated patients died during the trial, but the researchers report that no death was judged related to treatment.

The trial did not compare doses of memantine head to head, and questions remain. During the poster session at the meeting, many clinicians had questions about higher doses, and some said they were skeptical, having already seen adverse events in lower doses.

Dr. Grossberg responded to these questions during the session.

"We all have patients on memantine and maybe a combination — especially in middle or later stages of disease. Sometimes they do really well with the combination, and maybe over time they begin to not do as well and we no longer see the stabilizing effect we saw previously," Dr. Grossberg said. "In those individuals, I think 1 option is to go higher on memantine, and from this study, you at least know it's safe and well tolerated."

The new high-dose extended-release memantine option is currently under review by the FDA. Dr. Grossberg anticipates that it will be available in 2009. He does not yet know how much it might cost and says he hopes it will be comparable to current options.

This study was funded by Forest Pharmaceuticals.

American Neurological Association 133rd Annual Meeting: Poster T210. Presented September 23, 2008.

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