National Health Ministries is providing this update for information only, not to endorse or suggest this or any other pharmaceutical of therapeutic intervention. If you or someone you know is impacted by AD, you may want to consult the attending health care professional and ask to be given explanation of the specific action of this new drug as well as its appropriateness in your situation. The information contained here is of a fairly technical nature, however, we did not want to delay this announcement while we wait for information written in consumer terms. We anticipate that additional information will be available soon and will forward it as we receive it.

We do know that Alzheimer's patients suffer dysfunction of brain cells, which affects memory and thinking ability. Eventually the brain damage leads to death. An estimated 4.5 million Americans, most of them elderly, have Alzheimer's disease, according to the Alzheimer's Association.

Memory loss in Alzheimer's disease is due to a disturbance of messages in the brain. The brain contains so-called NMDA receptors that are involved in transmitting nerve signals—important in learning and memory. Memantine/Namenda® belongs to a group of medicines called NMDA receptor antagonists. It apparently causes the NMDA receptors to improve their ability to "pick-up" the transmission of nerve signals and consequently, one's memory.

Alzheimer's disease and some other types of dementia damage brain cells. The damage causes some cells to release too much of a chemical called glutamate, which carries messages between brain cells. Too much glutamate can damage cells further, because when it sticks to ‘docking sites' on the surface of a cell, too much calcium can get into the cell and damage it. Memantine/Namenda® sticks to the same docking sites, blocking glutamate, so that it can't let too much calcium in. The docking sites are called N-methyl-D-aspartate (NMDA) receptors, thus the drug is sometimes referred to as an "NMDA receptor antagonist."

The damage Alzheimer's disease causes to brain cells also reduces the supply of another brain chemical needed to carry messages called acetylcholine. The other drugs currently licensed for treating Alzheimer's disease all increase the amount of acetylcholine. Because the new drug works differently, it may be that the two types of drug could be taken together, and researchers are looking at whether this might be safe and effective.

Medications currently being prescribed for people with Alzheimer's disease, medications called cholinesterase inhibitors, continue to be used and researchers are continuing to study their effectiveness and safety. The four medications available in the United States today are tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®).

Memantine/Namenda® is licensed only for people with Alzheimer's disease who are in the moderately severe to severe stages of the illness. It is not licensed for people with other kinds of dementia, although some research is being done into whether it is effective for people with other types, such as vascular dementia. There are also ongoing studies on whether it could help people in the earlier stages of dementia.

This drug has been used for treating people with dementia in Germany for over ten years. Over the past few years studies have been done apparently demonstrating that it can be effective in helping people in the later stages of the illness.

While the new medication will not help everyone who tries it, one study showed that about two thirds benefited, to a greater or lesser extent. However, in the same study, around 45 percent of patients on placebo (dummy pill) also benefited. The study showed improvement in practical matters such as getting up, washing, getting dressed and going to the toilet. People who were helped by the drug needed less help from care givers. The drug also improved scores in tests of cognition (thinking and understanding).

Another study showed that both the group treated with Memantine/Namenda® and those on the placebo got worse over six months, but those on Memantine/Namenda® declined less 2. The results of the studies are averages, so some people did better and some worse than the average. It is not possible to tell whether the drug will have an effect for any particular person.

For more complete information about Alzheimer's disease go to
/healthy/ad-faq.htm.

The following additional information is fairly technical and was contained in an Alzheimer's Association Information Release, October 2003.

The Alzheimer's Association plans to update this information as more is known from recent clinical trials or from postmarketing experience with Memantine/Namenda®. The latest version of this fact sheet is always available by calling their 24/7 Contact Center at (800) 272-3900 or on their Web site www.alz.org/ResourceCenter/ByTopic/memantine.htm.

What is Memantine/Namenda®?
Memantine/Namenda® is a drug approved in October 2003 by the U.S. Food and Drug Administration (FDA) for treatment of moderate to severe Alzheimer's disease. Forest Laboratories Inc., Memantine's U.S. developer, will market the drug under the trade name Namenda®. Memantine was first approved in Germany for treatment of various neurological disorders in 1982, where it is marketed by Merz + Co. as Axura®. Since 2002, it has been approved in the rest of the European Union, where it is marketed by Lundbeck as Ebixa®. Forest Labs anticipates that Memantine/Namenda® will be available in U.S. pharmacies by early 2004.

What kind of drug is Memantine/Namenda®?
The technical description of Memantine/Namenda® is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, the first Alzheimer drug of this type approved in the United States. It appears to work by regulating the activity of glutamate, one of the brain's specialized messenger chemicals involved in information processing, storage, and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to allow a controlled amount of calcium to flow into a nerve cell, creating the chemical environment required for information storage.

Excess glutamate, on the other hand, over stimulates NMDA receptors to allow too much calcium into nerve cells, leading to disruption and death of cells. Memantine/Namenda® may protect cells against excess glutamate by partially blocking NMDA receptors.

Memantine/Namenda's® action differs from the mechanism of the cholinesterase inhibitors that were previously approved in the United States for treatment of Alzheimer symptoms. Cholinesterase inhibitors temporarily boost levels of acetylcholine, another messenger chemical that becomes deficient in the Alzheimer brain.

What is the evidence that Memantine/Namenda® may help Alzheimer symptoms?
Forest submitted evidence in support of Memantine/Namenda‘s® effectiveness in treating moderate to severe Alzheimer's disease in a new drug application to the FDA in December 2002, amended in January 2003. In September 2003, the FDA's Peripheral and Central Nervous System Drug Advisory Committee met to respond to specific questions raised by the FDA regarding application data. Briefing documents and summaries of advisory committee critiques are available on the FDA Web site.

At the conclusion of its meeting, the advisory committee voted unanimously that the following data submitted in the new drug application support the safety and effectiveness of Memantine/Namenda® in treating moderate to severe Alzheimer's disease:

1. A 28-week U.S. study enrolling 252 individuals with moderate to severe Alzheimer's disease and initial scores ranging from 3-14 on the Mini-Mental State Examination (MMSE). In this double-blind study, participants were randomly assigned to receive either 10 mg of Memantine/Namenda® twice a day or a placebo. Those receiving Memantine/Namenda® showed a small but statistically significant benefit in a test of the their ability to perform daily activities and on the Severe Impairment Battery, a test designed to measure cognition in profoundly incapacitated individuals. On the Clinician Interview-Based Impression of Change Plus Caregiver Input, a measure of overall function, Memantine/Namenda® recipients also showed a benefit that was significant in one analysis but not in another. In this study, when participants with MMSE scores of less than 10 were considered as a separate group, Memantine/Namenda® recipients showed no benefit compared to those who received placebo on either daily activities or overall function.
2. A 24-week U.S. study enrolling 404 individuals with moderate to severe Alzheimer's disease and initial MMSE scores from 5-14 who had been taking donepezil (Aricept®) for at least six months, with a stable dose for at least three months. In this double-blind study, participants were randomly assigned to receive either 10 mg of Memantine/Namenda® twice a day or a placebo in addition to their donepezil. Those receiving Memantine/Namenda® showed a statistically significant benefit in performing daily activities and on the Severe Impairment Battery, while participants taking donepezil plus placebo continued to decline.

Some advisory committee members considered Memantine/Namenda's® effect modest, similar in scope to the effect seen with cholinesterase inhibitors.

The advisory committee found problems with the design of a third submitted study, conducted in Latvia, because it enrolled individuals with vascular dementia as well as Alzheimer's disease. An additional issue was that although the data showed a positive effect for Memantine/Namenda® on reducing dependence on care, the study lacked an acceptable measure of effect on cognitive function. According to current FDA standards, drugs approved specifically to treat Alzheimer's disease must show a benefit on cognitive symptoms as well as on overall function, which confirms that the effect on cognition is clinically meaningful.

In June 2003, Forest reported preliminary results from another add-on therapy trial enrolling participants with mild to moderate Alzheimer's who were also taking any of three commonly prescribed cholinesterase inhibitors — donepezil (Aricept®), galantamine (Reminyl®), or rivastigmine (Exelon®). Data from this trial were not included in the new drug application seeking approval of Memantine/Namenda® for moderate to severe disease. According to the company, the data showed that participants receiving Memantine/Namenda® in combination with a cholinesterase inhibitor did not experience significantly greater benefit in cognition or overall function than those who received a cholinesterase inhibitor and a placebo. These preliminary results suggest that Memantine/Namenda® may not be as effective in individuals with mild to moderate Alzheimer's who are taking a cholinesterase inhibitor as it may in more severely ill individuals. This data has not yet been peer reviewed or presented in a professional forum.

According to a Forest official, the company expects to report data from two additional trials of Memantine/Namenda in mild to moderate Alzheimer's and another trial in treating moderate to severe disease by the end of 2003.

How is Memantine/Namenda® supplied and prescribed?
Memantine/Namenda® is supplied as an oral medication in 10 mg tablets. Forest Labs is providing prescribing information at www.namenda.com or by calling (877) 2-NAMENDA or (877) 262-6363.

Adverse effects occurring more commonly with Memantine/Namenda® than with placebo included headache, constipation, confusion, and dizziness.