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Memantine: Still a Poor Choice for Alzheimer’s Disease

Worst Pills, Best Pills Newsletter article May, 2016

Alzheimer’s disease is an irreversible, progressive disease of the brain that significantly impairs thinking, memory and — in the late stages — the ability to perform daily activities. It is the most common cause of dementia among the elderly, accounting for 60 to 80 percent of all dementia cases.[1],[2] Approximately 5.3 million people in the U.S. suffer from the disease, and by 2050, that number is expected to grow by nearly 10 million.[3]

Loved ones of patients suffering from...

Alzheimer’s disease is an irreversible, progressive disease of the brain that significantly impairs thinking, memory and — in the late stages — the ability to perform daily activities. It is the most common cause of dementia among the elderly, accounting for 60 to 80 percent of all dementia cases.[1],[2] Approximately 5.3 million people in the U.S. suffer from the disease, and by 2050, that number is expected to grow by nearly 10 million.[3]

Loved ones of patients suffering from dementia often are desperate for anything that might stop the disease. Drugmakers take advantage of this desperation, selling Alzheimer’s disease drugs through strategies based on hope, fear and guilt: hope that one of these drugs might work; fear that if one of these drugs is not started quickly, all will be lost; and guilt over not deciding to “fight” the disease with expensive, sometimes dangerous, drugs.

Memantine (NAMENDA) recently has been one of the drugs for Alzheimer’s disease most heavily promoted through direct-to-consumer advertising. Ads for the drug frequently air on television, including during this year’s Super Bowl.

You should ignore these ads. Like all other drugs approved for treating Alzheimer’s disease, memantine has been designated by Public Citizen’s Health Research Group as Do Not Use, primarily because there is no persuasive evidence that it is effective, making the drug’s known risks unacceptable.

Drug history

Memantine has been marketed in Europe since the 1980s. Since 1982, it has been sold in Germany for the treatment of Parkinson’s disease and other neurologic disorders. In 2002, the European Medicines Agency, an agency similar to the FDA, approved memantine for the treatment of Alzheimer’s disease.

The drug manufacturer suggests that memantine works by blocking the binding of the chemical glutamate to receptors in the brain (known as NMDA receptors) that may play a role in the destruction of brain cells in Alzheimer’s disease patients.[4]

Available in the U.S. since 2003, memantine was the first drug approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe Alzheimer’s-disease-associated dementia. Importantly, memantine is not approved by the FDA to treat mild forms of the disease.

Prior to memantine being marketed in the U.S., the FDA had approved four medications — all members of the drug family known as acetylcholinesterase inhibitors — for treatment of only mild to moderate Alzheimer’s disease: donepezil (ARICEPT), galantamine (RAZADYNE), rivastigmine (EXELON) and tacrine (COGNEX; no longer marketed in the U.S.). (Donepezil and a patch form of rivastigmine are now FDA-approved for severe Alzheimer’s disease.)

NAMZARIC, a combination of memantine and donepezil, was approved by the FDA in late 2014 for treatment of moderate to severe Alzheimer’s disease.

Serious adverse effects

Common side effects reported with memantine during clinical trials of the drug included dizziness, headache, constipation, pain and difficulty breathing.[5] Hallucinations and confusion also occurred slightly more often in memantine-treated subjects than in those receiving placebo pills.[6]

Following approval of the drug in Europe and the U.S., there have been rare reports of memantine-treated patients experiencing inflammation of the pancreas, kidney failure, toxic epidermal necrolysis (a blistering rash that can resemble severe burns), bone marrow failure (decreased ability to make blood cells), heart failure and liver failure.[7],[8] There also have been reports of seizures, high blood pressure, jerky movements, itching, nervousness, tremors, aggressive reactions and nausea.[9]

According to a 2007 article in the French drug safety journal Prescrire International on the dangers of memantine and other Alzheimer’s disease medications, adverse cardiovascular events such as cardiac arrest and bradycardia (slow heart rate) were the most frequent type of serious side effects reported. The article stated that “the potential benefits of these treatments are often too limited to warrant exposing patients to the risk of such serious adverse effects.”[10]

A 2008 study reviewed 36 cases of adverse cardiovascular events associated with memantine use. There were 18 cases of bradycardia and 18 cases of various other cardiovascular reactions.[11]

Meager benefit

FDA guidelines for approval of drugs to treat Alzheimer’s disease require that studies demonstrate a statistically significant beneficial effect on two primary measures: cognitive function and overall patient functioning, or activities of daily living. Memantine barely met these standards.

The FDA medical officer who reviewed clinical trial data submitted by the drug’s manufacturer prior to approval noted that the difference on measures of cognitive function between memantine-treated and placebo-treated subjects was “small.”[12]

Commenting on the measures of overall patient functioning for one clinical trial, the FDA medical officer also stated, “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.”[13]

Since the drug’s approval in the U.S., several medical journal reviews of memantine have concluded that it offers meager benefit to Alzheimer’s disease patients (see box below).

Assessments of Memantine’s Effectiveness
Prescrire International (2003): “Data on the effects of memantine in severe Alzheimer’s disease are sparse and weak. There is no evidence that memantine is effective in patients with severe dementia.”[14]

Drug and Therapeutics Bulletin (2003): “On published evidence, memantine produces, at best, only a small reduction in the rate of deterioration in global, functional, and cognitive scales in ... patients. Whether this translates into important changes in quality of life or how long the effects last is unclear.”[15]

Cochrane Database of Systematic Reviews (2006): “Memantine has a small beneficial effect [after] six months in moderate to severe [Alzheimer’s disease].”[16]

Prescrire International (2012): “Downgraded, at last! In 2011 the French Pharmacoeconomic Committee downgraded its rating of the medical benefit … provided by [memantine and three other Alzheimer’s disease drugs] from ‘major’ to ‘low,’ because … ‘the public health benefits of specific treatments for Alzheimer’s disease have still not been demonstrated …’ The Pharmacoeconomic Committee finally recognized that the available data failed to show a benefit of these drugs in most patients with Alzheimer’s disease.”[17]

A 2011 study found that there were no statistically significant differences between memantine and a placebo for any outcomes measured in patients with mild Alzheimer’s disease.[18] For those with a moderate form of the disease, there were small differences seen, but these clearly were not clinically important. The authors concluded, “Despite its frequent off-label use, evidence is lacking for a benefit of memantine in mild AD [Alzheimer’s disease], and there is meager evidence for its efficacy in moderate AD.”

Finally, the effect of memantine on the progression of the disease is summed up in the drug’s product labeling, which states: “At this time, there is no evidence that memantine prevents or slows neurodegeneration in patients with Alzheimer’s disease.”[19]

References

[1] National Institute on Aging. Alzheimer’s disease fact sheet. https://www.nia.nih.gov/alzheimers/publication/alzheimers-disease-fact-sheet. Accessed February 12, 2016.

[2] Larson EB. Evaluation of cognitive impairment and dementia. Last updated October 28, 2015. UpToDate.

[3] Alzheimer’s Association. 2015 Alzheimer’s disease facts and figures. Alzheimers Dement. 2015;11(3):332-384.

[4] Mani RB. Final briefing document for the September 24, 2003, meeting of the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee meeting: Efficacy review of the new drug application for memantine. August 19, 2003. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3979B1_05_FDA-Efficacy%20Review.pdf. Accessed February 14, 2016. Page 15.

[5] Boehm G. Briefing document for the September 24, 2003, meeting of the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee meeting: NDA safety review for memantine. August 20, 2003. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3979B1_04_FDA-Safety%20Review.pdf. Accessed February 14, 2016.

[6] Ibid. Page 6.

[7] Ibid. Page 4.

[8] DailyMed. Drug label for memantine. Updated October 30, 2013. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba. Accessed February 14, 2016.

[9] Memantine: New preparation. Poor evaluation and uncertain benefit in Alzheimer's disease. Prescrire International. December 2003;12(68):203-205.

[10] Anti-Alzheimer drugs: Life-threatening adverse effects. Prescrire International. February 2007;16(87):16.

[11] Gallini A, Sommet A, Montastruc JL. Does memantine induce bradycardia? A study in the French PharmacoVigilance Database. Pharmacoepidemiol Drug Saf. 2008;17(9):877-881.

[12] Mani RB. Final briefing document for the September 24, 2003, meeting of the Food and Drug Administration’s Peripheral and Central Nervous System Drugs Advisory Committee meeting: Efficacy review of the new drug application for memantine. August 19, 2003. http://www.fda.gov/ohrms/dockets/ac/03/briefing/3979B1_05_FDA-Efficacy%20Review.pdf. Accessed February 14, 2016. Page 7.

[13] Ibid. Page 41.

[14] Memantine: New preparation. Poor evaluation and uncertain benefit in Alzheimer's disease. Prescrire International. December 2003;12(68):203-205.

[15] Memantine for dementia? Drug and Therapeutics Bulletin. 2003;41(10):73-76.

[16] McShane R, Areosa Sastre A, Minakaran N. Memantine for dementia. Cochrane Database Syst Rev. 2006;(2):CD003154.

[17] Drugs for Alzheimer’s disease: best avoided. Prescrire International. 2012;32(340):105.

[18] Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol. 2011;68(8):991-998.

[19] National Institutes of Health. DailyMed. Memantine drug label. Updated October 30, 2013. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9f27baf-aa2a-443a-9ef5-e002d23407ba. Accessed February 14, 2016.