Namenda-Memantine is indicated for moderate to severe Alzheimer’s type dementia. FDA approved it on October 17, 2003. Memantine can be taken with or without food. It is given as 5 mg daily and recommended target dose is 20 mg per day and recommendations are to increase 5 mg every week till he starts taking 20 mg per day total. The minimum recommended interval between dose increases is one week. Consider dose reduction of Namenda in patients with moderate to severe renal impairment, because, Memantine is excreted through the tubular secretion. Memantine undergoes little metabolism, but majority of 57 to 82 percent is excreted unchanged in the urine. The remainder is usually converted primarily to three metabolites:
- N- gludantan conjugates
- 1-nitroso-deaminated Memantine
- 6-hydroxy Memantine.
These possess minimal NMDA receptor antagonism. CYP450 enzyme system does not play a significant role in metabolism. Terminal half-life is approximately 60 to 80 hours. Renal clearance involves active tubular secretion. In severe renal impairment, we need to reduce the dose of the medicine.
NMDA (N-methyl-D-aspartame). Persistent activity of NMDA receptors by glutamate that is excitatory amino acid has been hypothesizing to contribute to Alzheimer’s’ disease. Memantine exerts its therapeutic effect through its action as a low to moderate affinity of uncompetitive open channel NMDA receptor antagonist that binds preferentially to NMDA receptors operated cation channels. Memantine showed low to negligible affinity for GABA, Dopamine, histamine, benzodiazepine, adrenergic amines, and glycine receptors for voltage dependent calcium, sodium, magnesium or potassium channels. Memantine showed some antagonistic effect at 5-HT3 receptor with potency similar to that for the NMDA receptor and blocked nicotinic acetylcholine receptors with 1/6 to 1/10 the potency.
In vitro and one clinical study showed that Memantine does not effect acetylcholine esterase inhibitors: Aricept or Donepezil. In vitro, it did not inhibit acetylcholinesterase inhibitors, neither Donepezil nor Glantamine. Memantine or Namenda highly absorbed with peak concentration reaching at about 3 to 7 hours. It has no effect with food. It has low protein binding in the plasma that is 45%. The terminal elimination half-life is about 60 to 80 hours. Subjects with moderate to severe renal impairment will have significantly higher exposure than normal. Females have approximately 45% higher exposure because of the bodyweight. Condition that raise urine pH decreases elimination of Memantine. Memantine levels will be increased with increasing the urine pH. Several mechanism and the drugs such as carbonic anhydrase inhibitors, soda bicarb, renal tubular acidosis, and severe urinary tract infection alter urine pH. Take precautions in those conditions.
It is pregnancy category B (no evidence of risk in human), slight maternal toxicity with decrease pup weight was noted in the maternal rats. No adequate or well-controlled studies were done in pregnant women. We need to take precautions when Memantine is administered to nursing mothers or children, because safety and efficacy has not been established. Combined use of Memantine and other NMDA antagonist such as dextromethorphan, Ketamine, and Amantadine, has not been evaluated systematically. Take precautions.
If hydrochlorothiazide is given alone, it decreases the bioavailability of HCTZ by 20%. But if it is given with Triamterene, it did not affect the bioavailability. Under alkaline urine condition, there is 80% reduction of Memantine excretion. In Memantine, remember, 20-80 rules, 80% of this is excreted through urine, unchanged, and clearance is reduced by 80% under alkaline urine condition, and bioavailability of hydrochlorothiazide is decreased by 20%. If we alkalinize the urine, the excretion will be reduced, and there is a possibility of increased adverse reaction.
Adverse reactions: dizziness 7% compared to Placebo 5, confusion 6% compared to placebo 5%, headache 6% compared to placebo 3%, hallucination 3% compared to placebo 2%, somnolence 3% compared to placebo 2%, constipation 5% compared to placebo 3%, vomiting 3% compared to placebo 2%, coughing 4% compared to placebo 3%, dyspnea 2% where as placebo is 1%, hypertension 4% compared to placebo 2%, back pain 3% compared to placebo 2%, pain 3% compared to placebo 1%, fatigue 2% compared to placebo was 1%.
Adverse events that occur at least 2% in Memantine treated patient, but at a greater or equal rate compared to Placebo are agitation, falls, injuries, urinary incontinence, diarrhea, insomnia, bronchitis, influenza like symptoms, UTI, depression, gait abnormalities, URI (upper respiratory tract infection), anxiety, peripheral edema, nausea, anorexia, and arthralgia. Memantine has been administered to approximately 1350 patient, 1200 of those received maximum dose that is 20 mg per day for up to 884 days with 862 patients receiving at least 24 weeks of treatment and 383 patient receiving 48 weeks or more of the treatment. As far as overdose is concerned, there is one case with overdose up to 400 mg of Memantine, the patient experienced psychosis, restlessness, visual hallucinations, somnolence leading to stupor and loss of consciousness. The patient recovered without any permanent damage. We recommend contacting the poison control while continuing good supportive measures and symptomatic treatment. Do not forget elimination of Memantine can be enhanced by acidification of urine. Alkalinization of the urine increases the availability of Memantine.
Namenda has low to moderate, uncompetitive antagonist of NMDA receptor. It might have some neuroprotective effects in animals. Too much glutamate causes neurotoxicity because it is excitatory. There are several theories of Alzheimer’s, which include mitochondrial dysfunction secondary to inflammation, glutamate activity, and amyloid deposit, neurofibrillary tangles. The neurofibrillary tangles are inside the brain cells, and amyloid deposits outside the brain cells. Medications, which bind 90 to 95% of plasma protein, cause problems, but Memantine binds 45% only. Mini cognitive scale consists of three item recall, and clock drawing at specific time, numbers on the clock, and placing the hands right get them 2 points; and then 3 point recall 0-2 suggestive of dementia, 3-5 no dementia. Mini mental exam is a 30-point scale. Less than 25 suggest dementia. Score of less than 10 suggest severe dementia. The MMSE score of 10-20 is suggestive of moderate dementia. Above 20 is mild dementia.
Namenda helps with behavior, agitation, aggression, and delusions. If you remember the mnemonics BAD, B for behavior, A for agitation and aggression, and D is delusions. So, Namenda takes care of the BAD things. They are all better with Namenda. Namenda has low to moderate affinity, uncompetitive antagonist at NMDA receptor channels. It has shown neuroprotective in pre clinical models. Right now, we have four million people, who are afflicted with Alzheimer’s, but by the year 2050, there will be 16 million. More dramatic increase in patients above the age 85. DSM-4 definition of Alzheimer’s is memory loss plus at least one of the following such as apraxia, agnosia, aphasia, and disturbance of cognitive function. With severe impairment in social / work related functioning to a significant degree, and other potential causes of dementia were ruled out and there is no delirium.
During moderate to severe stages of dementia, memory loss continued to get worse, and the patient begins to fail to recognize people. These deficits lead to difficulties in instrumental activities of daily living. It affects the patient’s personalities and behavior as well. Memory, behavior, and cognition continued to get worse but it does not occur in stepwise fashion, except in vascular dementia. Memantine may improve learning and memory in animal models. Memantine might have neuroprotective action in pre clinical models. Abnormal glutamate or glutamatergic activity may cause neuronal toxicity and impaired learning. Abnormal glutamate or glutamatergic activity results in sustained low levels of activation of NMDA receptor. Clinical insult resulting in neuronal damage and loss in brain regions associated with learning and memory manifested as cognitive deficits. There is no evidence that Memantine prevents or slows neurodegenerative process in Alzheimer’s.
Memantine shows low to negligible affinity for GABA, Dopamine, and benzodiazepine receptors. Memantine blocks the damaging effect of abnormal glutamate activity while preserving physiological processes dependent on glutamate, such as learning and memory without causing serious side effects. Magnesium is a natural blocker in the ion channel pores. Magnesium is highly voltage dependent, which means it is easily and quickly displaced from the channel pore by depolarization. In contrast, Memantine when bound within the channel pore, remains so that during chronic depolarization, it continues to block excess calcium influx. When a cognitive event occurs, and depolarizes the neuron, Memantine quickly leaves the channel and allows the signal to be transmitted. In this manner, Memantine blocks pathologic, glutamatergic, signaling while allowing for physiological glutamatergic process. What it means is that it blocks the pathological glutamate activity allowing the physiological glutamate activity.
Memantine is 100% bioavailable. After oral administration, it reaches maximum concentration in three to seven hours. It has low plasma protein binding capacity that is 45%. T-max is 3 to 7 hours. T-half is 60-80 hours. Concentration in plasma at a steady state is 70 to 150 ng/ml achieved within 21 days. Mean CSF to serum ratio was 0.52. Memantine exhibits both linear and dose proportional kinetics at therapeutic doses. It can be administered with or without food, eliminated mostly in the urine as I said. The metabolites of Memantine are inactive. There is no or minimal effect on CYP-450 isoenzyme. No changes in the peak level or distribution of the medication with Donepezil. So, there is no interaction between them. No peak interactions with other drugs eliminated renally such as Dyazide, HCTZ with Triamterene. Dose should be reduced in patients with moderate to severe renal impairment. In severe renal impairment, the medicine was not evaluated yet. Practically there is not much drug interaction was seen.
Memantine is available in European countries, mainly in Germany since 1980. Merz evaluated Memantine for vascular dementia in 1990s, and they continued to evaluate. European approved the medicine in 2002. Development program for Alzheimer’s disease begin in mid 1990s. Pivotal clinical trials for FD approval conducted between 1990 and 2002. It is approved for treatment of moderate to severe Alzheimer’s disease in Europe under the trade name Ebixa in Germany, and Axura in rest of the Europe since May 2002. Approved by FDA in US for the treatment of moderate to severe Alzheimer’s disease under the trade name Namenda happened in October 2003. There are one million patients treated with Memantine as of year 2003.
Pivotal trials of Namenda—There are three randomized, parallel group, double blind, and placebo control trials. All of them were positive. Two of them studied Memantine is monotherapy and the other one is with the Donepezil, i.e. Aricept. Monotherapy in moderate to severe dementia, dose was 10 mg b.i.d., duration was 28 weeks. Mini mental status range was 3 to 14. Principal efficacy majors were CIBIC plus SIB (severe impairment battery), and ADCS-ADL 19. That study was published in New England Journal of Medicine in 2003 and was done by Reisberg and associates. Combination of Memantine and Donepezil was done by Dr. Pier Tarriot, published in JAMA in 2004, dose was 10 mg b.i.d., it was for 24 weeks, MMSC was 5 to 14, CIBC plus, SIB, and ABCS—ADL 19 were the efficacy majors. The third study by Winblad, published in International Journal of Geriatrics Psychiatry, 1999 was nursing home patient with dementia 10 mg once a day, 12 weeks’ duration, Mini metnal status range was less then 10, and global change was done by CGI-C, and functional scale was done by BGP-Care. SIB, ADCS-ADL 19 Alzheimer’s disease cooperative study—activities of daily living inventory and functional assessment scale that majors severely impaired dementia population. CIBIC plus clinicians interview based impression of change plus caregiver input assessment. It is a 7-point scale. And then, neuropsychiatric inventory 12 item scale, GDS (global deterioration scale), and
- Reisberg in New England Journal of Medicine published Memantine monotherapy in moderate to severe dementia in 2003, and there were 252 patients with moderate to severe dementia where the Mini mental status score was 3 to 14. Memantine was given 20 mg per day, four-week titration, and duration of the study was 28 weeks, and it is done as phase 3, multicenter study, and randomized double blind placebo control.
SIB and ADCS-ADL, and CIBIC plus, and NPI 12 item scale do principal efficacy majors. Patients were more than 50 years of age and diagnosis was done by DSM-4 criteria. CT and MRI scan consistent with AV i.e., atrophy and volume loss, functional assessment staging that is FAST score was more than 6A, and global deterioration scale stage is 5 and 6. Global deterioration scale is a 7-point scale, higher score correlates with greater impairment. Memantine treated patients were 126, placebo was 126, 97% completed the study in Namenda group, 84% completed study in placebo group, 33% withdrawal in placebo compared to 23% withdrawal in Namenda group. Over the six-month period, Memantine patients decreased the SIB score by 3.9 points, whereas placebo patients decrease by 9.8 points. Therefore, Memantine patients have significantly less cognitive decline on SIB, total score compared with placebo. On the activities of daily living ADCS-ADL 19 Memantine patients decline by approximately three points, while placebo patients decline by approximately five points, and ADL is a 19 item including, eating, walking, toileting, bathing, grooming, dressing, and attending the conversation, doing household activities, and traveling beyond home.
In Dr. Reisberg’s study, New England Journal of Medicine year 2003, the CIBIC plus patients receiving Memantine were rated significantly better at 28 weeks than the placebo group. Mean CIBIC plus score at 28 week for placebo was 4.74, whereas Memantine was 4.38. CIBC plus was 7-point scale, 1 being marked as improvement, 7 being marked as worsening. As far as behavior is concerned, on neuropsychiatric interview, it did show significant difference between the treatment groups in favor of Memantine in delusions agitation, and aggression. Memantine monotherapy conclusions were that Memantine treatment was associated with the less decline versus placebo on cognition function and global change. Cognition is SIB, function is ADCS-ADL 19, and global change is CIBIS plus majors, published by Reisberg in New England Journal of Medicine in 2003.
- Second study by Pier Tariott, published in JAMA in 2004 is Memantine in patients receiving Donepezil that was published in January 2004 in JAMA. It is designed as phase 3 trial, multicentral, and in US randomized, double blind placebo control study 404 outpatients with moderate to severe dementia with mini Mental status between 5 and 14, Memantine was given 20 mg per day that is 10 mg b.i.d. with four week titration. Duration of the study was 24 weeks. Principal efficacy majors were SIB, ADCS-ADL, CIBC plus, and NPI, published in JAMA in 2004 by Tariott. 202 patients received Memantine and Donepezil i.e., Aricept and 202 patients received placebo and Donepezil. 85 % completed the study in Memantine, 15% completed withdrawal in Memantine group. 75% completed in placebo plus Donepezil and there was 25% withdrawal.
Results in cognition i.e., SIB, Memantine end point was +1.1 showing improvement above baseline, whereas placebo end point was -2.3 and it is statistically significant. The SIB scores of less than 63 are considered to be very severely impaired, which corresponds to Mini Mental Status examination of less than 4. In activities of daily living, there was statistically significant difference in function at the end point between treatment group with Memantine and Aricept compared to placebo and Aricept in favor of Memantine 3.2 point decline in placebo group where as 1.8 decline in Memantine group. Global change CIBIC plus, the Memantine plus Donepezil group, was consistently rated better at each time point compared to placebo plus Donepezil.
The results of combination therapy as published in JAMA in 2004 by Pier Tariott, the patients treated with Memantine and Donepezil perform significantly better on cognition, functional, global, and behavioral outcome majors, compared with patients treated with Donepezil alone. The patient’s treated with Memantine and Donepezil for six months appeared to show a sustained improvement in cognitive function. The combination was well tolerated with rates of overall dropout and dropout for adverse events favoring the Memantine treated groups. As far as neuropsychiatric inventory is concerned, Memantine and Donepezil treated groups show significantly reduce the frequency and severity of the agitation and aggression, irritability and labile compared with the Placebo and Donepezil—Tariott in JAMA 2004.
- Third study is Memantine nursing home patient, published by Winblad, International Journal of Geriatrics Psychiatry, in 1999. Eastern European Phase III multi center randomized double blind placebo control study, 167 nursing home patients with severe primary dementia or vascular dementia Mini Mental Status examination of less than 10. Memantine was given 10 mg per day, or placebo two-week titration, from 5 mg to 10 mg. Duration f the study was 12 weeks; principal efficacy majors were BGP-Care, CGI-C, and D test. BGP is behavioral and functional disturbances in geriatric patients. D test was designed to evaluate function in geriatric patients. This D test evaluates motor cognitive social behavior and ADL in geriatric population. Memantine group has 82 patients, placebo has 84, 78% completed Memantine in Memantine group, 5% withdrawal; placebo completed 95%, 5% withdrawal.
In BGP, behavioral and functional geriatric patient battery shows a mean change from baseline from 5.3 compared to 3.3 in placebo treated patients. The difference was statistically significant. CGI-C score, which is global change in the nursing home patients with dementia, showed Memantine treated patient was 3.1 compared to 3.5 for placebo treated patient. Results of function that is D test shows improvement in ability to standing up, mobility, ability to move, ability to wash, ability to shower themselves, ability to dress, eat, fluid intake, toilet use, communication, understanding, expression, orientation in space, recognition of persons, group activities, hobbies and interests, and behavior. From D test evaluate daily function in geriatric patients. Each item was rated at 6-point scale with higher number indicating more severe impairment. Across all 16 items, there was positive trend in Memantine group, 9 were clinically significant. Improvement was noted in patient’s activities of daily living such as getting up washing, getting dressed, and going to the toilet, and there is clinically relevant and significant decrease in dependency on nursing staff in favor of Memantine.
As far as adverse events are concerned, dizziness is the most common, but it was reported as mild. Memantine decrease agitation, falls, and accidental injuries. Correlate in discontinuation of Memantine compared to placebo was much less. There were no much serious adverse events. Memantine i.e., Namenda 10 to 20 mg per day is safe and well tolerated in elderly patient with moderate to severe dementia. Although, confusion was reported in a great number of Memantine treated patients, it was rated as mild and transient, and occurred at a medium of 32 days, and remitted within two weeks. There was no clinically relevant difference Memantine and Placebo treated group as far as adverse event profile is concerned, there were no vital sign changes, there were no laboratory parameters to be monitored, EKG values did not change, at a dosage 20 mg per day, it was safe and well tolerated.
Memantine is the first of the only NMDA receptor antagonist for the treatment of moderate to severe dementia. Memantine is effective treatment as monotherapy or in combination with acetylcholinesterase inhibitors such as Aricept. Memantine has been proven effective as a first line monotherapy in the treatment of moderate to severe Alzheimer’s disease. Memantine plus Donepezil statistically improved the global major of cognition, function, and behavior compared with Donepezil alone. Memantine is safe with excellent tolerability. Memantine has low potential for drug-drug interaction.
Namenda dosing and administration, week one 5 mg once a day, week two 10 mg per day, such as 5 mg twice a day, week three 10 mg in the morning 5 mg in the evening, and week four was 10 mg twice a day, can be administered with and without food. In patients with severe renal impairment, use of Namenda has not been systematically evaluated, and is not recommended. To facilitate proper dosing, during the titration, Namenda titration pack helps us a lot. For additional information, please call 1-877-2-Namenda (1-877-2-6263632), or visit www.namenda.com.
Assessment methods
For staging, we use Mini Mental Status examination, MMSE, FAST is functional assessment staging, and GDS global deterioration scale.
For cognition, we use cog.
SIB is severe impairment battery.
AD cog is Alzheimer’s disease assessment scale, cognitive subscale.
For function, we do ADCS-ADL (Alzheimer’s disease cooperative study-Activities of daily living).
ADCS-ADL 19 is the same with 19-point scale for ADL.
BGP care dependency is the behavior rating scale for geriatric patient care dependency sub scale.
D test is modified version of D test is an 16 item G2 scale for motor cognition, social, behavior, and social activities of daily living.
For global change, we use CIBIC plus CGI and BGP total. So, CIBIC plus clinicians interview based impression of change with caregiver input, and CGIC, clinical global impairment of change. And BGP is behavior-rating scale for geriatric patient, care dependency sub scale.
As far as behavior is concerned, neuropsychiatric inventory.
BPRS, brief psychiatric rating scale.
AD-noncog, Alzheimer’s disease assessment scale non-cognitive subscale.
Thank you,
M. A. Kazmi, M.D.
MAK/ahk
7-10-04
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