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`ISSN 0025 - W556
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`Volume 40. Number 8, August 2004
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`' P
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`ROUS SCIENCE
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`IPR2015-00410
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`IPR2015-00410
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`ndexeéiwiln MEDLINE®, ISI® SciSearch, Research Alert and Current Contents/Clinical Medicine;
`BASE/Excerpta Medica; Biosciences Information Service Biological Abstracts;
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`Editorial Board
`- R. Mannhold (Germany)
`Editor
`- Y. Abiko (Japan)
`- M. Neuman (France)
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`~ L. de Angeiis (Italy)
`Ft. Nikolov (Bulgaria)
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`P. Buckley, (USA)
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`R. Cacabelos (Spain)
`M. NOgradi (Hungary)
`P.H. Chandrasekar (USA)
`GM. Pasinetti (USA)
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`G. Eastland (USA)
`J.T Pento (USA)
`Assistant Editors
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`' L- Fairley
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`‘ X. Rabasseda
`- B. Solomon (Israel)
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`‘ K. Shedrick
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`‘ L.A. Sorbera
`- M.B.H. Youdim (Israel)
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`Drugs of Today is a peer-review journal
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`Doptlrtght‘0 2004 Prous SCIence S.A. — Reproduction in whole or part is not permitted except by written permission from the Publisher.
`epomo Legal B. 11.454.1965 — Printed in Spain — ISSN: 0025-7656
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`IPR2015—00410
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`Drugs of Today 2004, 40 (8): 685-695
`Copyright© 2004 PROUS SCIENCE
`CCC: 0025-7656/2004
`
`MEMANTINE HYDROCHLORIDE
`Pharmacological and clinical profile
`
`Hans J. Mobius 1, Albrecht Stoffler 1 and Stephen M. Graham 2
`
`1 Merz Pharmaceuticals, Frankfurt, Germany; 2Forest Laboratories, Jersey City, New Jersey, USA
`
`CONTENTS
`Summary ............................................... 685
`Introduction: NMDA receptor antagonists for dementia treatment. ..... 686
`Memantine history ........................................ 687
`Chemical characteristics .................................... 687
`Memantine pharmacodynamics ............................... 687
`Pharmacokinetic profile ..................................... 688
`Clinical efficacy data in dementia ............................. 689
`Recent clinical data in other indications ......................... 690
`Safety and tolerability ...................................... 691
`Regulatory status ......................................... 692
`References .............................................. 692
`
`i I
`
`i:
`
`Summary
`Memantine (Axura®, Merz Pharmaceuticals
`GmbH; Ebixa®, H. Lundbeck A/S, Namenda™,
`Forest Laboratories, Inc.) is an uncompetitive N(cid:173)
`methyl-o-aspartate (NMDA) receptor antagonist
`with low to moderate affinity for the (+)MK-801 bind(cid:173)
`ing site. It is characterized as a voltage-sensitive
`open-channel NMDA receptor blocker that antag(cid:173)
`onizes NMDA receptor-mediated inward currents
`in vitro with an IC50 of 1-3 1-1M. In animal models,
`
`Correspondence: Hans J. Moebius, MD, PhP, Chief
`Scientific Officer, Merz Pharmaceuticals GmbH, Ecken(cid:173)
`heimer Ldstr. 100, 60318 Frankfurt Main, Germany. Tel.:
`+49 69 1503 311; FAX: +49 69 1503 399.
`E-mail: hj.moebius@ merz.de
`
`memantine displays both neuroprotective (antiexci(cid:173)
`totoxic) and cognition-enhancing properties at ther(cid:173)
`apeutically relevant concentrations. The strong volt(cid:173)
`age dependency and rapid blocking/unblocking ki(cid:173)
`netics of memantine are thought to be the basis for
`its excellent clinical tolerability.
`Recently completed clinical studies demonstrate
`positive effects of memantine in Alzheimer's dis(cid:173)
`ease both as a monotherapy and in patients re(cid:173)
`ceiving continuous donepezil treatment. Meman(cid:173)
`tine treatment also has demonstrated significant
`improvement of cognitive performance in patients
`suffering from vascular dementia. Furthermore, the
`safety and tolerability of memantine in clinical trials
`has been excellent, with the incidence of prema(cid:173)
`ture withdrawals due to adverse events no greater
`
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`686
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`Pharmacological and clinical profile of memantine hydrochloride
`
`than placebo and overall low frequencies of total
`adverse events. In 2002, memantine was approved
`by the European Medicines Agency (EMEA) for the
`treatment of moderately severe to severe Alzhei(cid:173)
`mer's disease. More recently, memantine was ap(cid:173)
`proved in the US for the treatment of moderate to
`severe Alzheimer's disease (October 2003). Here,
`we review the most recent pharmacological and
`clinical data in dementia patients that has emerged
`from the systematic evaluation of memantine. ©2004
`Prous Science. All rights reserved ..
`
`Introduction: NMDA receptor antagonists
`for dementia treatment
`Dementia is a serious risk to aging individuals
`and places an enormous burden on healthcare
`systems in modern societies. Alzheimer's disease
`accounts for the majority of dementia cases, fol(cid:173)
`lowed by vascular dementia and dementia of the
`Lewy-body type. Alzheimer's disease is character(cid:173)
`ized by intellectual deficits leading to functional im(cid:173)
`pairment and eventually complete-care dependen(cid:173)
`cy. The main risk factor for Alzheimer's disease is
`age: the incidence of Alzheimer's disease increas(cid:173)
`es from 0.5% per year at age 65 to 8% per·year at
`age 85 (1 ). The prevalence of Alzheimer's disease
`also increases with age and may reach up to 47%
`in the very old (85 or more years) (2).
`Until recently, approved treatments in Alzhei(cid:173)
`mer's disease have focused on cholinergic neuro(cid:173)
`transmission, as loss of cholinergic neurons is ob(cid:173)
`served in the process of Alzheimer's disease and
`is correlated with memory impairment. In the last
`decade, other neurotransmitter systems have been
`implicated in addition to the cholinergic hypothesis
`of Alzheimer's disease, and inhibition of patholog(cid:173)
`ical glutamatergic activity has emerged as a promis(cid:173)
`ing therapeutic approach for the treatment of pa(cid:173)
`tients with Alzheimer's disease (3, 4).
`Glutamate is the principal excitatory amino acid
`neurotransmitter in cortical and hippocampal neu(cid:173)
`rons. There is increasing evidence that cortical de(cid:173)
`mentia with neuronal dysfunction may result, in
`part, from sustained elevation of glutamate levels
`and/or increased sensitivity of glutamate receptors
`to synaptic glutamate, leading to low-level, pro(cid:173)
`longed influx of calcium into neurons, impaired
`neuronal homeostasis and, eventually, neurode(cid:173)
`generation (5-9). Excessive glutamate rel·ease,
`with consequent neuronal dysfunction or even de(cid:173)
`generation, follows cerebral energy deficit and hy(cid:173)
`poxia (1 0). Additionally, hyperactivity of the gluta-
`
`matergic input to the hippocampus may result in
`excessive excitability of hippocampal cells, leading
`to disturbances in the signaling pathways thought
`to be critical for memory and learning.
`One of the receptors activated by glutamate is
`the N-methyl-o-aspartate (NMDA) receptor, which
`has been found to be involved in learning and
`memory (11, 12). When activated, NMDA receptors
`allow calcium influx into neurons, which appears to
`be critical for the cellular processes involved in
`learning and memory. Overstimulation of NMDA re(cid:173)
`ceptors, however, can lead to excessive calcium
`influx, which ultimately results in neurodegenera(cid:173)
`tion and cell death (13, 14). Under such conditions,
`temporally uncoordinated, tonic stimulation of NMDA
`receptors produces enhanced synaptic noise and
`deficits in synaptic plasticity and learning. Indis(cid:173)
`criminate tonic stimulation of NMDA receptors re(cid:173)
`sults in increased frequency and amplitude of post(cid:173)
`synaptic miniature potentials. It is postulated that
`this increased pathological synaptic noise, or chat(cid:173)
`ter, impairs the ability of the synapse to recognize
`and transmit physiological signals, leading to de(cid:173)
`ficits in synaptic plasticity and learning. Therefore,
`agents that selectively block pathological but not
`physiological activation of the NMDA receptor might
`restore the function of hippocampal neurons and
`improve memory-related symptoms of Alzheimer's
`disease (15).
`The clinical development of several NMDA re(cid:173)
`ceptor antagonists was abandoned or had never
`been considered due to serious adverse effects,
`mainly psychotomimetic and cardiovascular in na(cid:173)
`ture. The NMDA receptor antagonist memantine is
`a clinically well-tolerated treatment, and it is the on(cid:173)
`ly compound targeting the glutamatergic system in
`dementia that has been extensively tested in clini(cid:173)
`cal studies. Memantine is a low to moderate affini(cid:173)
`ty, uncompetitive NMDA receptor antagonist with
`strong voltage dependency and rapid blocking/un(cid:173)
`blocking kinetics. Given these pharmacological fea(cid:173)
`tures, it is hypothesized that memantine blocks the
`sustained activation of NMDA receptors by iJM
`concentrations of glutamate under pathological
`conditions, but rapidly leaves the NMDA receptor
`channel upon transient physiological activation by
`low mM concentrations of synaptic glutamate (16,
`17). These pharmacological properties are thought
`to be the basis for the excellent safety and tolera(cid:173)
`bility of memantine in clinical use, differentiating
`memantine from other NMDA receptor antagonists.
`
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`H.J. Mobius, A. Steffler and S.M. Graham
`
`689
`
`Memantine and metabolites are excreted pre(cid:173)
`dominantly by the kidneys, and to a small extent,
`by bile and feces. Changes in urinary flow have no
`clinically relevant influence on renal excretion, but
`renal excretion is around 7-9-fold higher at acidic
`urine pH compared to alkaline conditions. A small
`quantity of memantine is eliminated via sebaceous,
`lachrymal, salivary and sweat glands.
`
`Plasma levels in patients
`Plasma samples for memantine levels were
`taken at steady state in phase Ill trials. The dose(cid:173)
`related plasma concentrations are similar to those
`observed at steady state in younger, normal volun(cid:173)
`teers (70-150 ng/ml, or 0.5-1 J.LM, with 20 mg me(cid:173)
`mantine per day), with the standard deviation indi(cid:173)
`cating that there is relatively high interindividual
`variability.
`
`Clinical efficacy data in dementia
`Oral memantine monotherapy has been evalu(cid:173)
`ated in randomized, placebo-controlled trials in
`adult patients with moderate to severe Alzheimer's
`disease (21 ), severe dementia due to Alzheimer's
`disease or vascular dementia (53), and milder
`forms of vascular dementia (22, 23). Additionally,
`the combination of memantine and donepezil ver(cid:173)
`sus donepezil monotherapy was recently evaluat(cid:173)
`ed in adult patients with moderate to severe Alz(cid:173)
`heimer's disease (24).
`The first of these more recent studies, started
`by Winblad and Poritis in 1994 and published in
`1999 (the M-BEST study), investigated memantine
`in 166 care-dependent nursing home patients with
`severe dementia (Mini Mental State Exam [MMSE]
`<1 0 and Global Deterioration Scale [GDS] stages
`5-7) due to either Alzheimer's disease or vascular
`dementia (53). Primary efficacy endpoints were a
`clinical global rating by the investigator (CGI-C)
`and a quantitative assessment of activities of daily
`living and behavior by the nurses ("Beurteilungs(cid:173)
`skala tor geriatrische Patienten" [BGP], subscore
`care dependency). After 12 weeks of treatment
`with 1 0 mg/day memantine or placebo, there was a
`statistically significant advantage for memantine(cid:173)
`treated patients on both of the primary endpoints,
`as well as on the D-scale, a rating of functional per(cid:173)
`formance of the patients by the investigator.
`
`Studies in Alzheimer's disease
`Reisberg et al. (21) conducted a 28-week, dou(cid:173)
`ble-blind, randomized, controlled trial of the effica-
`
`cy of memantine in patients with moderate to se(cid:173)
`vere Alzheimer's disease at 32 centers throughout
`the US. Patient eligibility criteFia included: a diag(cid:173)
`nosis of Alzheimer's disease by NINCDS-ADRDA
`criteria, GDS stages 5 or 6, Functional Assessment
`Staging (FAST)= 6 and MMSE score of 3-14. A to(cid:173)
`tal of 252 patients were randomized to memantine
`(10 mg b.i.d.; n = 126) or placebo (n = 126). At week
`28, memantine-treated patients showed signifi(cid:173)
`cantly less decline (p <0.05) than placebo-treated
`patients on both primary outcome assessments:
`the Alzheimer's Disease Cooperative Study-Activi(cid:173)
`ties of Daily Living Inventory modified for a severe
`patient population (ADCS-ADL19) (54, 55) and the
`Clinicians' Interview-Based Impression of Change
`Plus Caregiver Input (CIBIC-Pius) (56). Both change
`in cognition, based on Severe Impairment Battery
`(SIB) scores (57), and change in FAST scores (58)
`favored memantine treatment (p <0.01 ). Further(cid:173)
`more, memantine treatment was safe and well tol(cid:173)
`erated. The overall discontinuation rate was 29%,
`and the most common reasons for discontinuation
`were adverse events (1 0% memantine; 17% place(cid:173)
`bo) and withdrawal of consent (10% memantine;
`11% placebo).
`Data from this trial were further analyzed in a
`study in which ADCS-ADL19 scores were used to
`classify patients as dependent (n = 1 06) or auto(cid:173)
`nomous (n = 146) based on their basic and instru(cid:173)
`mental ADL capabilities. It was found that patients
`treated with memantine were more than 3 times as
`likely to remain autonomous after 6 months than
`placebo-treated patients (odds ratio = 3.03). Me(cid:173)
`mantine thus appears to slow progression of mod(cid:173)
`erate to severe Alzheimer's disease (59).
`Moderately severe to severe dementia places a
`very heavy burden on caregivers and on health(cid:173)
`care resources. An indirect measure of the clinical
`relevance of the results seen in these memantine
`clinical trials was obtained by determining the ef(cid:173)
`fect of memantine versus placebo treatment on es(cid:173)
`timates of caregiving time and on rate of institu(cid:173)
`tionalization. There was a strong correlation be(cid:173)
`tween nursing time for basic care (representing
`58% of nursing time) and the BGP care dependen(cid:173)
`cy subscore (r = 0.81 ). In the M-BEST study, 66%
`of memantine-treated patients showed clinically
`relevant improvements on the BGP care depen(cid:173)
`dency subscore. Although not tested directly, this
`would be anticipated to translate into reduced care(cid:173)
`giver time. In fact, in the study published by Reis(cid:173)
`berg eta/. (21 ), caregiving time was measured (60)
`
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`11
`
`690
`
`Pharmacological and clinical profile of memantine hydrochloride
`
`and a reduction in mean monthly time of more than
`50 hours was seen with memantine treatment com(cid:173)
`pared to placebo (p = 0.02). Furthermore, a signifi(cid:173)
`cant reduction in institutionalization at week 28 for the
`memantine group compared to the placebo group (1
`vs. 5 patients, respectively; p = 0.04; TPP subset)
`was observed, although the number of patients eval(cid:173)
`uated in this community-based study was small.
`A recent 24-week, double-blind, placebo-con(cid:173)
`trolled, multicenter US trial evaluated memantine
`(1 0 mg b.i.d. titrated over a 4-week period) versus
`placebo in 404 moderate to severe Alzheimer's
`disease outpatients on continuous cholinesterase
`inhibitor therapy (donepezil 5-10 mg/day) for more
`than 6 months (24). Patients' MMSE scores at
`baseline were 5-14. The two treatment groups
`were randomized with regard to baseline parame(cid:173)
`ters and the mean MMSE total score was 10.1 at
`baseline (24). Efficacy endpoints in this study were
`similar to those published by Reisberg eta/. (21 ),
`with the primary efficacy parameters being a mea(cid:173)
`sure of cognitive function and a measure of activi(cid:173)
`ties of daily living. At study endpoint, patients re(cid:173)
`ceiving memantine/donepezil treatment improved
`in cognitive function above baseline (assessed with
`the SIB}, whereas donepezil/placebo-treated pa(cid:173)
`tients continued to decline (p <0.001 ). Patients who
`received memantine treatment showed significant(cid:173)
`ly less decline in daily function (assessed with the
`ADCS-ADL19} than donepezil!placebo-treated pa(cid:173)
`tients (p = 0.02}. Furthermore, there was a signifi(cid:173)
`cant improvement in global patient status (mea(cid:173)
`sured by the CIBIC-Pius) in favor of memantine at
`week 24 (p = 0.03). In both of these studies, meman(cid:173)
`tine had a positive effect on various subscores of the
`Neuropsychiatric Inventory (NPI} and, specifically,
`was found to reduce agitation/aggression (61 ).
`Forest Laboratories, Inc., recently announced
`that results of a phase Ill US study of memantine
`monotherapy in mild to moderate Alzheimer's dis(cid:173)
`ease demonstrated a statistically significant differ(cid:173)
`ence versus placebo on the primary efficacy mea(cid:173)
`sures of cognition and global patient status. The
`double-blind, parallel-group, placebo-controlled
`phase Ill study was designed to evaluate the safe(cid:173)
`ty and efficacy of memantine given as monothera(cid:173)
`py at a daily dosage of 1 0 mg twice daily to patients
`with mild to moderate Alzheimer's disease over a
`period of 6 months. The US study was conducted
`at 42 centers and included a total of 403 patients.
`Patients receiving memantine performed signifi(cid:173)
`cantly better than patients receiving placebo on
`
`both primary outcome measures: the Alzheimer's
`Disease Assessment Scale-cognitive subscale
`(ADAS-cog) (p = 0.003) and the CIBIC-Pius (p =
`0.004). While ADAS-cog scores revealed worsen(cid:173)
`ing cognitive function in placebo-treated patients,
`an improvement was seen in the memantine group.
`CIBIC-Pius scores showed less decline in global
`measures among memantine-treated patients. Me(cid:173)
`mantine was well tolerated; patients experienced
`adverse events at overall rates that were compara(cid:173)
`ble to placebo (62}.
`
`Studies in vascular dementia
`Support for the cognitive improvement seen in
`the Alzheimer's disease clinical trials is provided by
`two studies (MMM500 and MMM300} performed in
`patients with mild to moderate vascular dementia.
`Although the vascular dementia trials included a
`different range of dementia severity than the previ(cid:173)
`ously mentioned Alzheimer's disease studies, the
`data are relevant for the evaluation of the specific
`cognitive effects of memantine.
`MMM500 and MMM300 were double-blind,
`placebo-controlled, multicenter studies involving a
`total of 900 patients with mild to moderately severe
`(baseline MMSE 1 0-23} probable vascular demen(cid:173)
`tia according to NINDS-AIREN criteria (22, 23). Pa(cid:173)
`tients were randomized to receive either 1 0 mg
`memantine twice daily or placebo over a period of
`28 weeks. In both trials the primary efficacy pa(cid:173)
`rameters consisted of a cognitive endpoint (ADAS(cid:173)
`cog) and a global endpoint (CGI-C in MMM500,
`CIBIC-Pius in MMM300). Memantine was signifi(cid:173)
`cantly superior to placebo in both studies on the
`ADAS-cog. Results on the CGI-C and CIBIC-Pius
`were not significant between treatment groups.
`
`Recent clinical data in other indications
`
`AIDS dementia
`Navia eta/. (63} reported some positive effects
`on cognitive symptoms in patients with AIDS-relat(cid:173)
`ed cognitive impairment.
`
`Pain
`Contrasting reports exist concerning the effects
`of memantine on neuropathic pain. While Eisenberg
`eta/. (64) did not find a significant treatment effect of
`20 mg/day memantine in patients with postherpetic
`neuropathia, several brief reports do show positive
`effects for memantine on other neuropathic pain con(cid:173)
`ditions (65--67). It remains unclear whether higher
`doses are needed for this indication.
`
`IPR2015-00410
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`H.J. Mobius, A. Stoffler and S.M. Graham
`
`691
`
`Safety and tolerability
`The safety information summarized is derived
`from an updated integrated summary of safety
`(ISS) that was provided to the US Food and Drug
`Administration in April, 2003, for the memantine
`New Drug Application. Included in this brief sum(cid:173)
`mary are data from eight phase 11/111 double-blind,
`placebo-controlled trials in dementia (Alzheimer's
`disease and vascular dementia) and four open-la(cid:173)
`bel extensions of these trials. Of the 1862 total pa(cid:173)
`tients in these core trials, 940 were treated with
`memantine and 922 were treated with placebo. In
`addition to the core dementia trials, clinical trials of
`memantine in patients with various neurological
`disorders (including peripheral neuropathy, Par(cid:173)
`kinson's disease, multiple sclerosis and spasticity)
`have been conducted. A total of 2297 patients
`have been exposed to memantine, with 1244 pa(cid:173)
`tients receiving placebo, in 27 clinical trials. Based
`on results from these trials, memantine is a safe
`and well-tolerated treatment.
`
`Core double-blind,
`placebo-controlled dementia trials
`Patients in these trials were well matched de(cid:173)
`mographically by age, sex, race, weight, height
`and MMSE scores. A comparable number of me(cid:173)
`mantine patients (662 out of 940) and placebo pa(cid:173)
`tients (624 out of 922) reported an adverse event.
`Dizziness, confusion, headache and constipation
`were reported in over 5% of memantine patients
`and at an incidence greater than that found for
`placebo (Table 1). Most adverse events were con(cid:173)
`sidered mild or moderate in severity, and not relat(cid:173)
`ed to the trial drug. Furthermore, the overall pro(cid:173)
`files of adverse events reported by patients in ei-
`
`Table /. Most frequently reported adverse events (?.5%)
`in all double-blind, placebo-controlled, phase IIIII/ de(cid:173)
`mentia trials.
`
`Adverse event
`
`Dizziness
`Agitation
`Confusion
`Headache
`Constipation
`Fall
`Accidental injury
`
`Memantine
`(N = 940) n (%)
`
`Placebo
`(N = 922) n (%)
`
`64 (6.8)
`63 (6.7)
`58 (6.2)
`54 (5.7)
`50 (5.3)
`48 (5.1)
`44 (4.7)
`
`49 (5.3)
`98 (10.6)
`42 (4.6)
`31 (3.4)
`28 (3.0)
`50 (5.4)
`64 (6.9)
`
`N = number of patients receiving treatment; n = number
`of patients reporting a particular adverse event.
`
`ther treatment group were not affected by demen(cid:173)
`tia diagnosis or severity.
`The most common reason for discontinuation
`from the core dementia trials was the incidence of
`an adverse event, reported by 10.1% of meman(cid:173)
`tine patients and 11.5% of placebo patients. In one
`of the trials in which memantine was administered
`to patients receiving continuous donepezil therapy
`(24), memantine treatment resulted in fewer dis(cid:173)
`continuations due to an adverse event compared
`to placebo (7.4% vs. 12.4%, respectively). In the
`open-label extension studies, the percentage of all
`patients who discontinued the trials was 17.9%,
`with 10.7% reporting the occurrence of an adverse
`event as the reason for discontinuation. The most
`common adverse events associated with trial dis(cid:173)
`continuation in the open-label trials were pneumo(cid:173)
`nia (1.2%) and cerebrovascular disorder (1.2%).
`
`Postmarketing surveillance studies
`In addition to the clinical program that was the
`basis for both EU and US approval, postmarketing
`surveillance studies of memantine in "dementia
`syndrome" were performed in Germany. In the first
`of these, 1420 patients treated with memantine,
`usually at doses of 1 Q-20 mg/day, were followed
`for more than one year (68). Memantine signifi(cid:173)
`cantly improved memory, concentration, orienta(cid:173)
`tion, mood, sleep and motor functions compared to
`baseline. Memantine was rated as 'very well' or
`'well' tolerated in 94% of cases at the end of the ob(cid:173)
`servation period. The most frequently reported ad(cid:173)
`verse events were restlessness (1.3%), nausea
`(0.9%), dizziness (0.8%) and fatigue/tiredness or
`sleep disorders (0.4%).
`In another study, 531 care-dependent patients
`were treated with memantine up to 30 mg/ day for
`a mean of 44 days (69). In total, 401 (76%) showed
`clinical global improvement (measured by CGI-C),
`with 240 (45%) showing 'significant' improvement
`and 161 (30%) showing 'moderate' improvement.
`Functional capacities (ADL) also improved. Me(cid:173)
`mantine was well tolerated; only 3% of the patients
`reported adverse events (n = 16), with restless(cid:173)
`ness being the most frequent symptom.
`An additional postmarketing surveillance study
`was conducted in the German market to obtain
`safety data on combinations of memantine and
`cholinesterase inhibitors (70). Data from 158 pa(cid:173)
`tients (aged 26-100 years) with a median meman(cid:173)
`tine dose of 20 mg/day, most of whom suffered
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`H.J. Mobius, A. Stoffler and S.M. Graham
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