rivastigmine for alzheimer’s disease

Drug Profile

10.1586/14737175.5.5.563 © 2005 Future Drugs Ltd ISSN 1473-7175 563www.future-drugs.com

Rivastigmine for Alzheimer’s diseaseAbhilash K Desai† and George T Grossberg

†Author for correspondence3211 E Northshore Boulevard, 157, Appleton, WI 54915, USATel.: +1 920 720 3870Fax: +1 902 720 [email protected]

KEYWORDS: Alzheimer’s disease, cholinesterase inhibitors, dementia, ENA-713, exelon, rivastigmine

Alzheimer’s disease is the most common form of neurodegenerative dementia and poses considerable health challenges to both patients and their families. Rivastigmine is a powerful slow-reversible, noncompetitive carbamate cholinesterase inhibitor that is approved for the treatment of mild-to-moderate Alzheimer’s disease. Randomized, double-blind, placebo-controlled trials of up to 6 months duration have shown beneficial effects of rivastigmine compared with placebo in measures of cognition and global functioning. Less rigorous but growing data suggest that the beneficial effects may endure for up to 5 years, extend to more advanced stages of Alzheimer’s disease and may occur in noncognitive domains, such as activities of daily living and the behavioral symptoms of Alzheimer’s disease. Evidence from controlled studies also supports the use of rivastigmine for cognitive and behavioral symptoms in Alzheimer’s disease associated with vascular risk factors, dementia with Lewy bodies and Parkinson’s disease dementia. Early and continued treatment of Alzheimer’s disease with rivastigmine maximizes the observed beneficial effects. The most prominent adverse effect of rivastigmine is centrally mediated cholinergic gastrointestinal events, which can be minimized by slower dose-escalation intervals and administration with a full meal. Therapeutic dosing is 6–12 mg/day given twice daily, with higher doses having the potential for greater benefits.

Expert Rev. Neurotherapeutics 5(5), 563–580 (2005)

Dementia is characterized by both cognitiveand noncognitive dysfunction resulting in theimpairment of functional abilities. Cognitivedysfunction is characterized by impairment ofnew learning, short-term memory, judgment,language, visuospatial skills, alertness, motiva-tion and other higher cortical functions. Non-cognitive dysfunction is characterized bybehavioral disturbances [1]. The majority ofpatients with dementia experience neuropsy-chiatric symptoms over the course of the dis-ease. In one study, 75% of dementia patientsexhibited a behavioral or psychologic symptomin the past month (62% were clinically signifi-cant): 55% reported two or more disturbancesand 44% reported three or more disturbancesin the previous month [2]. The most frequent ofthe disturbances were apathy (36%), depres-sion (32%) and agitation/aggression (30%).Dementia is a major public health concern due

to the increasing life expectancy and growth ofthe aging population. As this populationexpands, cases of dementia will correspond-ingly increase and place unparalleled demandson the health and personal care services. Theprojected rapid growth of the aging popula-tions of underdeveloped nations is likely to leadto the further expansion of cases beyond thosemodeled on the aging of populations inindustrialized nations.

Alzheimer’s disease (AD) is a chronic neuro-degenerative disorder. It is the most commoncause of dementia in older adults. It affectsapproximately 25 million people worldwideand death is expected within 4–8 years(range: 2–20) of diagnosis [3]. This time framemay extend as cases are diagnosed earlier. Thelifetime risk of AD is 12–19% for women over65 years of age and 6–10% for men of thesame age. This may differ among ethnic

CONTENTS

Overview of the market

Introduction to the compound

Chemistry

Pharmacodynamics

Pharmacokinetics

Clinical efficacy

Other dementias

Mild cognitive impairment

Conclusions

Expert commentary

Five-year view

Key issues

References

Affiliations

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Desai & Grossberg

564 Expert Rev. Neurotherapeutics 5(5), (2005)

groups, with the risk being higher in African–American peopleand some Hispanic groups [4,5]. Age is the strongest risk factorfor AD. Prevalence of the disease is 2–3% in the 65–70 year oldage group, doubles with every additional 5 years of age and pla-teaus at an age of 85 years and over [6]. Annual costs in the USAalone are estimated to approach US$100 billion when consid-ering medical and long-term care as well as the lost productivityof caregivers [7].

In the brains of people with AD, the pathologic signs includedeposits of extracellular amyloid-β (Aβ) peptide in diffuseplaques and in plaques containing elements of degeneratingneurons, known as neuritic plaques [8]. Intracellular changesinclude deposits of abnormally hyperphosphorylated tauprotein, a microtubule assembly protein, in the form ofneurofibrillary tangles (NFTs). Loss of neurons and synapses isalso widespread [8].

The cause of AD is unknown. Although the amyloidhypothesis is currently the basis for several research studiesaimed to design and test treatments to prevent or delay AD,growing evidence indicates that AD may be a vascular, ratherthan a neurodegenerative, disorder [9]. There is evidence to sug-gest that chronic brain hypoperfusion is linked to AD risk fac-tors, preclinical detection and the pharmacotherapeutic actionsof AD symptoms [9].

There are three clinical stages of AD: mild, moderate andsevere. There is no cure for AD. Early diagnosis and interven-tion with therapies that may slow disease progression are likelyto represent an important component of effectivetreatment [10]. Although much progress has been made in thisarea, there are currently no clinically approved interventions forAD that are classed as disease-modifying or neuroprotective.

As with any type of dementia, irrespective of the underlyingetiology, the symptoms of AD are, to a considerable extent,related to impaired neurotransmission and degeneration ofneuronal circuits in the specific brain areas affected. AD is asso-ciated with the loss of neurons in the cerebral cortex and deple-tion of several cholinergic, monoaminergic and peptidergicneurotransmitters. Amongst all the neurotransmitters, cholin-ergic deficits are the greatest and of central importance in thepathogenesis of AD. Acetylcholine (ACh) is a neurotransmitterproduced in cholinergic neurons for release into the synapticcleft where it subsequently binds with both nicotinic and mus-carinic ACh receptors. Free ACh is hydrolyzed by acetyl-cholinesterase (AChE) and butyrylcholinesterase (BuChE) intoits constituents, choline and acetate. A host of cholinergicabnormalities, including alterations in choline transport, AChrelease, nicotinic and muscarinic receptor expression,neurotrophin support and perhaps axonal transport, have beenidentified in people with AD [11]. In AD patients, there is lossof basal forebrain cholinergic neurons and their projections,particularly in the neocortex, hippocampus and amygdala, witha global impact on higher cognitive functions such as learning,memory and executive functioning, as well as on behavior,neuropsychiatric function and emotional responses. CorticalAChE activity was found to be more robustly associated with

functions of attention and working memory compared withperformance on primary memory tests in AD [12]. Presynapticnicotinic receptors not only control the release of ACh, but alsoother neurotransmitters important for memory and mood,such as glutamate, serotonin and norepinephrine. It has beenshown that the reduction in the number of ACh receptorsprecedes other pathologic changes [13].

Cholinergic dysfunction may contribute to cognitive impair-ment indirectly by interfering with attentional processing [14]. Ithas been suggested that symptoms such as the impairment ofattention and concentration, anxiety, restlessness and hallucina-tions, delineate a specific central cholinergic deficiency syn-drome (CDS) that may be a better target for suchtreatment [15]. Changes in the quantitative electroencephalo-gram, muscarinic subtype radioimaging and serum anticholin-ergic activity may potentially help to diagnose the CDS.Among all the approaches investigated to increase cholinergictransmission (e.g., precursors to augment ACh synthesis, directagonists and ChEIs), the ChEI approach has been the mostsuccessful. ChEIs prevent the degradation of ACh and therebyamplify its postsynaptic action.

In AD, neurons undergo a prolonged state of injury and dys-function before the manifestation of clinical symptoms. Bio-logic onset of the disease may precede the detection of physicaland clinical manifestations by 20–40 years. By the time apatient sees a healthcare provider for memory problems, thepathophysiologic process is usually at a relatively advancedstage. In the predementia phase of AD, cognitive deficits, per-sonality changes (e.g., apathy) and mood changes (e.g., depres-sion) have been described [10]. Mild cognitive impairment(MCI) is a relatively broad clinical condition that, in manycases, represents a transitional state between normal cognitionand AD [16]. Criteria for MCI include an adult with subjectivecomplaints of memory loss, memory test scores one standarddeviation (SD) below age-adjusted normals, no significantobjective loss of function and a failure to meet the diagnosticcriteria for dementia [17]. This is in contrast to patients withage-associated memory impairment (AAMI), who have subjec-tive complaints of memory loss but normal psychometricscores. In total, 10–15% of patients with MCI per year (50%over 5 years) will develop dementia [17]. There is a significantdifference in AChE activity in the hippocampus betweengroups of controls, those with MCI and early AD patients.Recent data also suggest that differences in cholinergic deficitsbetween mild-to-moderate AD and MCI may serve to distin-guish between clinical and preclinical forms of AD [18]. Patientswith MCI experience a high prevalence of neuropsychiatricsymptoms [2]. In this study, 43% of MCI participants exhibitedneuropsychiatric symptoms in the previous month (29% ratedas clinically significant), with depression (20%), apathy (15%)and irritability (15%) being the most common symptoms [2].Much research is currently being conducted on MCI, since anytherapy that is effective at treating this early manifestation ofAD may provide an opportunity for managing the disease whilepatient function is relatively preserved.

Rivastigmine

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Along with improving cognition, reducing behavioral distur-bances in patients with AD, including apathy, depression, anxi-ety, hallucinations, delusions, agitation, aggression and disinhi-bitionis, is an important treatment goal. Neuropsychiatricdisturbances are distressing to the patient, who experiences fear,sadness or anxiety; are a source of marked distress for the care-giver; can cause greater impairment in activities of daily life(ADL) and may precipitate institutionalization [1]. Thus, thetreatment of behavioral disturbances in AD may ameliorate apatient’s emotional distress and have secondary beneficialeffects on the caregiver, and on the opportunity for the patientto remain at home.

Overview of the marketPhysostigmine was the first ChEI evaluated in the treatment ofAD, but its short half-life, unpredictable oral bioavailability, poorcentral penetration and dose-limiting adverse effects have limitedits usefulness [19]. Five drugs are currently approved for the treat-ment of AD. Of these, four (tacrine [Cognex™], donepezil [Ari-cept®], rivastigmine and galantamine [Reminyl® and Raza-dyne®]) belong to the class of drugs called ChEIs and areapproved for mild-to-moderate AD. Although belonging to thesame class, the four ChEIs have many clinically relevant differ-ences in terms of their chemical structure, mode of action andpharmacokinetics. The fifth drug, memantine, belongs to a dif-ferent class of drugs called the NMDA-receptor modulators andis approved for the treatment of moderate-to-severe AD. Tacrinewas the first ChEI approved for treating AD. Tacrine inhibitsboth AChE and BuChE, but is rarely prescribed because it causesan elevation in liver enzymes in nearly a third of patients (there-fore requiring hepatic monitoring in all patients) [20]. It is nowrarely used in clinical practice.

The second ChEI to come to the market was donepezil. Itbelongs to the piperidine class of compounds. Donepezil is ahighly selective reversible ChEI [21]. A number of short-term,randomized, placebo-controlled trials showed that donepezilprovided significant cognitive benefits in patients with mild-to-moderate AD [22], but a recent 2-year randomized, double-blindtrial showed no significant benefits with donepezil comparedwith placebo in time to institutionalization and progression ofdisability [23]. In this study, there were no significant differencesin behavioral symptoms, caregiver well-being and caregiver timecosts at end point. However, cognitive measures favoreddonepezil throughout the study. Donepezil has the longest dura-tion of action amongst currently available ChEIs. Once-dailydosing is possible due to a half-life of 70 h. It has 96% plasmaprotein binding and food has no effect on the rate or extent ofabsorption. Donepezil is metabolized by the cytochrome P450(CYP) liver enzyme system.

Rivastigmine, a sustained inhibitor of both AChE andBuChE, was the third ChEI to come to the market, and is thefocus of this drug profile.

The most recent ChEI to be approved in the USA for thetreatment of mild-to-moderate AD is galantamine.Galantamine is a natural phenanthrene alkaloid, a reversible

AChE (but not BuChE) inhibitor and an allosteric modulatorof presynaptic nicotinic cholinergic receptors [24]. A number ofshort-term, randomized, placebo-controlled trials showed thatgalantamine provided significant cognitive benefits in patientswith mild-to-moderate AD [25]. Galantamine has a serum half-life of approximately 8 h but only requires twice-daily dosing.It has 19% protein binding and food delays its rate but notextent of absorption. Galantamine is metabolized by the CYPliver enzyme system.

The only non-ChEI approved for the treatment of AD ismemantine. Memantine is a noncompetitive antagonist of theNMDA receptor for the excitatory neurotransmitter glutamateand is approved for use in moderate-to-severe AD. More researchhas been conducted with memantine on non-AD than ADpatients. Memantine has been shown to slow cognitive and func-tional decline in patients with advanced AD [26,27]. It is not acompetitor to rivastigmine or other ChEIs because it has a differ-ent mechanism of action and can be used in combination with aChEI. The combination of memantine and donepezil has beenshown to be superior to memantine and placebo on cognitiveand behavioral measures in this same patient population [28].

Antiamyloid therapies are still in the preliminary stages ofdevelopment and, if found useful, may be available for routineclinical use in a few years [29]. More studies are currently under-way on other compounds, such as nerve growth factor, for thetreatment of AD [30].

Introduction to the compoundThe discovery and development of rivastigmine arose from thesearch for a novel AChE inhibitor with enhanced clinical effi-cacy and improved pharmacokinetic and pharmacodynamicproperties, compared with earlier compounds. Rivastigminebelongs to the carbamate chemical class and has a distinctchemical structure relative to other AChE inhibitors [31].Rivastigmine is approved in the USA and in over 40 countriesin Europe, Asia, and North and South America for thetreatment of mild-to-moderate AD.

ChemistryRivastigmine is chemically known as (S)-N-ethyl-N-methyl-3-[1–1(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate. Rivastigmine tartrate is commonly referred toin the pharmacologic literature as SDZ ENA 713 or ENA 713.The molecular formula of rivastigmine is C14H22N2O2.C4H4O4and the molecular weight is 400.43. In addition to the activecompound, rivastigmine capsules contain hydroxypropyl methyl-cellulose, magnesium stearate, microcrystalline cellulose andsilicone dioxide. Each hard-gelatin capsule contains gelatin,titanium dioxide and red and/or yellow iron oxides.

PharmacodynamicsRivastigmine reversibly inhibits the metabolism of AChE, pref-erentially in the CNS [32]. It also has dose-dependent effects onAChE inhibition. It binds to both the esteratic and ionic sitesof AChE, preventing the enzyme from metabolizing ACh.

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Rivastigmine also inhibits BuChE, another cholinesteraseenzyme (FIGURE 1) [31,32]. Whereas tacrine, donepezil and galan-tamine are rapidly reversible agents, rivastigmine is classified asa pseudoirreversible (very slowly reversible) agent due to itslong inhibition of AChE for up to 10 h despite a very short(2 h) elimination half-life. This is because the carbamyl moietyof rivastigmine dissociates from AChE much more slowly thanthe acetyl moiety of ACh. Rivastigmine lacks binding affinityfor dopaminergic, opioid, muscarinic, nicotinic, and α- andβ-adrenergic receptors [31]. Preclinical studies in gerbils and ratsrecorded beneficial effects of rivastigmine in preventing delayedneuronal death, enhanced ACh brain concentrations andneuroprotective actions [31]. This could be of potential benefitin patients with ischemic stroke or head injury.

Acetylcholinesterase & butyrylcholinesteraseAChE and BuChE are carboxylic ester hydrolases present in thebrain. In the CNS, AChE is located mainly in neurons andBuChE is primarily associated with, and secreted from, glialcells. Approximately 80% of cholinesterase activity is due toAChE and its function is to metabolize ACh at synapsesthroughout the nervous system. BuChE has more generalactions in the brain that are less well understood. There are sev-eral molecular isoforms of AChE and BuChE that can bedivided into two classes (globular and asymmetric) on the basisof the absence and presence of a collagen-like tail [33]. The glob-ular forms consist of one, two and four catalytically active sub-units (designated G1, G2 and G4), whereas the asymmetricforms contain 4–12 catalytic units attached to a membrane-anchored collagen tail (A4, A8 and A12). In the normal brain,G4 is the most common form for both AChE and BuChE, fol-lowed by G1. Levels of G4 decline as AD progresses until theG1 forms of both enzymes become the more common. Rivastig-mine selectively and predominantly inhibits the G1 forms; thus,its activity cannot be measured in red blood cells, which onlypossess the G4 forms of cholinesterase, and its inhibitory effectsmay become selectively greater as AD progresses. There ispreliminary evidence that the glutamatergic system may bemodulated by rivastigmine via AChE inhibition [34].

BuChE activity extends to all hippocampal, cortical and tha-lamic areas known to receive cholinergic innervatoin and has adistinctly different pattern of distribution to AChE [35]. Inhuman amygdaloid nuclei, BuChE activity is more commonthan AChE among cholinesterase-positive neurons and in thehuman hippocampus the two enzymes coexist. In the thalamus,BuChE activity, as with AChE, is found in nuclei related tocognitive and behavioral functions. Although BuChE repre-sents only 10% of total ChE activity in the temporal cortex ofthe healthy human brain, as AD progresses, AChE activitydecreases by up to 45% and BuChE activity increases by40–90%. The ratio of BuChE to AChE may change from0.6 to as high as 11.0 as AD progresses. Increases in BuChEactivity are greater in the hippocampus than in the temporallobe in patients with AD. This is of particular importance giventhe key role of hippocampal atrophy and the related cholinergic

deficit in core cognitive areas of AD. As dual inhibitors of bothAChE and BuChE, rivastigmine and tacrine may provide maxi-mum preservation of ACh levels independent of the changingcontributions of AChE and BuChE to ACh hydrolysis as ADprogresses. Results with rivastigmine show that cognitiveimprovements (measured using the computerized neuropsycho-logic test battery) correlate independently with the inhibitionof AChE and BuChE in the cerebrospinal fluid (CSF) of ADpatients, suggesting that inhibition of both enzymes is a highlydesirable feature of AD therapy [36]. BuChE can, and does, takeover function to metabolize ACh at the synapse when AChE islost, a phenomenon that has been demonstrated in an AChEknockout mouse model and that probably occurs in AD [37].

There is accumulating evidence suggesting that BuChE con-tributes to disease progression in people with dementia, whichmay be particularly important in individuals with more severedementia [35]. This may pose a theoretical benefit for ChEIs thathave dual inhibition (AChE and BuChE), such as tacrine andrivastigmine, over ChEIs that only inhibit AChE, such asdonepezil and galantamine, especially as AD progresses. AChEand BuChE are associated with amyloid plaques and neurofibril-lary tangles in both AD and elderly individuals without signifi-cant cognitive impairment. Advanced plaques show as much as87% BuChE reactivity, compared with less than 20% reactivityin early, diffuse deposits. The presence of BuChE appears to dis-tinguish the neurotoxic plaques seen in the AD brain from thoseobserved in normal aging. Also, there is laboratory evidence thatBuChE may be needed to activate amyloid in humans [35] andBuChE may play a role in the phosphorylation of tau [38]; thismay have the potential for disease-modifying effects by ChEIsthat inhibit this enzyme. Finally, recent studies have demon-strated an association between the presence of BuChE variantswith reduced activity and a significantly slower rate of cognitivedecline [39] and also a positive correlation between reduced cogni-tive decline and levels of BuChE enzyme in the temporal cortexin patients with dementia [40]. These studies indicate thepotential importance of the BuChE genotype in theepidemiology of AD and progress of cognitive impairment.

Rivastigmine causes sustained inhibition of AChE andBuChE in the CSF as well as plasma in AD patients for12 months [41]. Although the mechanism behind this long-termeffect is as yet unknown, it may be a result of the slow dissocia-tion from target enzymes. After 12 months of treatment withrivastigmine (mean dose at 12 months: 11.8 mg/day), AChEand BuChE activities decreased from baseline by 46 and 65%,respectively. The sustained CSF inhibition of both AChE andBuChE by rivastigmine contrasts with findings after long-termtreatment by the reversible ChE inhibitors tacrine, donepeziland galantamine, which appear to increase levels of their targetenzyme AChE after prolonged treatment [42].

PharmacokineticsAbsorption & distributionRivastigmine is absorbed rapidly and completely after oraladministration in healthy adults, with time to maximum

Rivastigmine


concentration (Tmax) from 0.8 to 1.67 h and an absolute bio-availability of approximately 36% [43]. This suggests that pre-systemic biotransformation is high, indicating a significantfirst-pass effect. The decarbamylated metabolite of rivastig-mine is also rapidly detected within 2 h after administration.Food slows the absorption of rivastigmine (Tmax is delayed by90 min) and decreases the maximum concentration byapproximately 30%, with a subsequent increase in area underthe curve (AUC) of 30%. Taking rivastigmine with foodenhances its bioavailability and increases tolerability;

gastrointestinal (GI) adverse effects may be associated withhigh peak plasma levels. Protein binding is quite low at 40%,and 40–50% of the drug is associated with red blood cells.Rivastigmine is reported to be widely distributed with avolume of distribution of 1.8–2.7 l/kg and that of itsmetabolite being 4.3–5.9 l/kg [43].

Metabolism & eliminationRivastigmine is metabolized by its target enzymes AChE andBuChE at the synapse. Breaking the covalent bonds,

Figure 1. Hypothetical mode of action of rivastigmine.ACh: Acetylcholine; BuChE: Butyrylcholinesterase; CAMP: Cyclic adenosine monophosphate; ChAT: Choline acetyltransferase; CoA: Coenzyme A; EAACI: Excitatory amino acid carrier 1; MR: Muscarinic receptor; NR: Nicotinic receptor; mRNA: Messenger RNA; R: Rivastigmine; X: Inhibition.

ACh

ACh

AChACh

MR NR

Choline+ acetate Choline

+ acetate

Benignamyloid

Malignantamyloid

Acetyl CoA+ choline

Benignamyloid

Malignantamyloid

Tau

Phosphorylatedtau

MR NR

CAMP,1P3 Ca+2

Increase in EAACImRNA expression

Increased clearance ofexcess glutamate from synapse

Reduced phosphorylationof tau

Decreased productionof malignant amyloid

Postsynaptic nerve terminal

Presynapticnerve terminal

Secondmessengers

AChEBuChE

R

AChE R

R

RBuChER

ChAT

Synaptic cleft

Desai & Grossberg


rivastigmine forms with AChE and BuChE through hydrolysisby esterases. This is the first and most important step in thedegradation of this drug. The metabolite undergoes N-demethylation and/or sulfate conjugation in the liver. Theagent’s elimination half-life is less than 2 h (mean 1.64 h at adosage of 6 mg twice daily) [31]. Elimination is more than 90%complete 24 h after administration, and less than 1% isdetected in the feces, with most eliminated renally. In patientswith AD, aged between 50 and 92 years, no difference in drugexposure or absorption was found with age.

Hepatic & renal impairmentIn patients with renal and moderate hepatic impairment,rivastigmine AUC was found to be 1.4- and 2.3-fold higher,respectively, than in healthy controls [31]. The metabolite AUCwas 0.8-fold lower in renally impaired patients but 1.5-foldhigher in those with hepatic impairment. No significant differ-ences in elimination half-life were found between healthy con-trols and patients with moderate or severe renal impairment.The metabolite’s elimination half-life was longer only inpatients with severe renal impairment versus healthy volunteers.Although rivastigmine’s AUC was twice as high in hepaticallyimpaired patients, the change may be due to plasma proteins,altered fluid balance in various body compartments, reducedrenal blood flow and other nonmetabolic conditions. There-fore, specific dosing changes are not necessary in patients withrenal or hepatic impairment. The agent has not been evaluatedin patients with severe hepatic impairment and thus, it shouldbe used cautiously in such patients.

Drug interactionsSince rivastigmine has low protein binding and is metabolizedby its target enzymes, rather than by hepatic microsomal CYPisoenzymes, pharmacokinetic drug–drug interactions of clinicalimportance are unlikely [44]. Pooled data from placebo-control-led clinical trials in 2459 individuals (n = 1696 rivastigmine,n = 763 placebo) demonstrated no clinically significant druginteractions between rivastigmine and 22 classes of concomi-tant medications (e.g., anti-inflammatory, cardiovascular andantidiabetic drugs) commonly prescribed to the elderly [45].The other two commonly used ChEIs (donepezil and galan-tamine) are metabolized via CYP in the liver, thus have a poten-tial for pharmacokinetic drug–drug interactions with otheragents metabolized through the CYP system [21,24]. In theExpert Consensus Guidelines for the treatment of dementia,caution or extra monitoring when combining donepezil orgalantamine with fluoxetine, fluvoxamine (a monoamineoxidase inhibitor), nefazodone, paroxetine (a tricyclic anti-depressant), carbamazepine, ketoconazole and tramadol (andwhen combining galantamine with codeine) isrecommended [46]. Low protein binding of rivastigmine com-pared with donepezil may be an advantage in elderly patientswith low albumin, such as malnourished patients and thosewith renal and hepatic failure. Donepezil has high proteinbinding (96%) and in patients with low albumin, it carries a

higher risk of adverse effects and may displace other drugs withhigh protein binding, such as valproate, digitalis, warfarin andtolbutamide, with subsequent adverse effects.

Interactions with drugs that have an effect on the cholinergicsystem could be expected, as rivastigmine is metabolized bycholinesterases and causes cholinesterase inhibition. Loss oftherapeutic efficacy may occur when rivastigmine isconcomitantly used with anticholinergic medications.

Dose titration scheme in pivotal trialsA total of four Phase III trials have been conducted withrivastigmine for AD [47–50]. Of these, two used the same doseregimens, a maximum tolerated dose between 1–4 and6–12 mg/day [47,48]. The third trial had fixed doses of 3, 6 and9 mg/day [NOVARTIS PHARMACEUTICALS, UNPUBLISHED DATA]. Thefourth trial had titration to highest tolerated dose between2–12 mg/day in two or three divided doses [NOVARTIS PHARMA-

CEUTICALS, UNPUBLISHED DATA]. The results for the 1–4 mg/dayand the 3 mg/day groups were combined in the analyses as a1–4 mg/day group. Similarly, the 6–12 mg/day and 6 and9 mg/day treatment groups were combined in the analyses as a6–12 mg/day group.

Safety & tolerabilityAdverse effects in the 6-month pivotal trials that were signifi-cantly higher for the 6–12 mg/day group versus placebo at theend of the titration period included nausea (17–48%), vomit-ing (16–27%), anorexia (9–20%) and diarrhea (11–17%). Amuch lower rate of occurrence was observed during the mainte-nance phases. Completion rates for placebo and rivastigmine1–4 and 6–12 mg/day were 75–87, 74–86 and 66–76%,respectively. Adverse effects were the main reason for drop-outs.In total, 13% of rivastigmine patients discontinued due toadverse effects as compared with 4% of placebo patients.Weight loss was observed in some patients, most likely relatedto GI side effects (mean 1.78 kg rivastigmine, mean 0.05 kgplacebo; a significant difference but probability was notreported) [47]. Later studies and experience in clinical practicehave suggested that side effects are considerably reduced if up-titration is slowed to monthly and rivastigmine is taken onlyafter full meals. These side effects are not mediated through thestomach lining but rather they are due to too-rapid elevationsof ACh in the brain, which act upon the putative vomitingcenter in this organ. Thus, they are centrally, not peripherally,mediated [49]. GI side effects can also be improved by antiemet-ics. In one study, trimethobenzamide was effective in prevent-ing nausea and vomiting in 89% of patients [49]. The successrate was lower with glycopyrrolate (33%) and ondansetron(50%). For patients who have discontinued the drug for longerthan 1 week, it is recommended that they retitrate up to theirtherapeutic dose as a precaution. Besides GI adverse effects,there were statistically significantly higher numbers of events ofheadache, syncope, abdominal pain and dizziness amongpatients taking high-dose (6–12 mg/day) rivastigmine thanamong those taking placebo [50]. All adverse effects were typical

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of those associated with ChEIs. Follow-up assessments ofpatients at 26 weeks who had discontinued rivastigmine forvarious reasons at earlier times during three large, double-blind,placebo-controlled trials revealed no evidence for accelerateddeterioration or support for a withdrawal syndrome [32].

Data from more than 3000 subjects worldwide indicate thatthe drug is associated with no serious laboratorychanges (hepatic, renal, hematologic or biochemical) orelectrocardiographic and cardiorespiratory changes [31].

Rivastigmine (as well as other ChEIs) carries a theoretical riskof precipitating bradycardia and symptoms of syncope and diz-ziness through its effect on the heart via the peripheral para-sympathetic nervous system. The heart is naturally rich inAChE, and its inhibition may affect cardiac function, especiallyin older patients, many of whom have concomitant cardiovas-cular disease. Analysis of pooled 12-lead electrocardiographicdata from four Phase III studies showed that rivastigmineappears not to produce adverse effects on cardiac function [51].

Serious adverse events were GI hemorrhage and angina [31].However, their frequencies did no differ significantly from thoseon placebo. Reports of drug overdose (highest dose 46 mg)noted mild to moderate vomiting and diarrhea, which resolvedspontaneously [52]. Other symptoms during overdose were syn-cope, urinary and fecal incontinence, and tongue fasciculations,which resolved within 24 h of supportive treatment.

G4 AChE is the predominant form in the periphery and par-ticularly at the presynaptic membrane of the skeletal–neuro-muscular junction. Rivastigmine may have a low potential forcausing extrapyramidal symptoms due to a relative lack of G4AChE inhibition in the striatum, which has been supported byvarious studies in patients with dementia with Lewy bodies(DLB) and Parkinson’s disease dementia (PDD) exhibiting ahigh level of parkinsonian symptoms at baseline [53–55].

ContraindicationsRivastigmine is a carbamate derivative and is thereforecontraindicated in patients with carbamate hypersensitivity.

Clinical efficacyAlzheimer’s diseaseA systematic review to assess clinical efficacy of rivastigmine inAD was conducted by the Cochrane group in 2001 [52]. Thereview included four Phase III, double-blind, randomized con-trolled trials involving 3370 patients [47,48,NOVARTIS PHARMA-

CEUTICALS, UNPUBLISHED DATA]. Pivotal trials evaluated rivastig-mine for the treatment of mild-to-moderate AD, but not severedisease. Since AD can only be diagnosed definitively by brainautopsy, trials included patients defined as probably having thedisease. Eligibility criteria for potential subjects included meet-ing the criteria of the National Institute of Neurological andCommunicative Disorders and Stroke and the Alzheimer’s dis-ease and Related Disorders Association (NINCDS-ADRDA)for probable AD and a Mini-Mental State Examination(MMSE) score of 10–26 [56,57]. Two primary indicators of drugresponse for dementia recognized by most regulatory

authorities are Alzheimer’s Disease Assessment Scale – cogni-tion section (ADAS–Cog) and the Clinician’s Interview-Basedimpression of Change (CIBIC)-Plus. The ADAS–Cog, aninstrument that assesses memory, praxis and language, has pre-viously been demonstrated to reliably measure change inpatients with mild-to-moderate stage AD [58]. The ADAS–Cogscore ranges from 0 to 70, with a higher score from baselineindicating decline in cognition (memory, language, orientationand simple tasks). Only the patient is assessed. The CIBIC-Plusis an instrument where an experienced clinician assesses globalfunction (cognition, ADL and behavior) based on interviewswith the patient and caregiver. Using this information, the clin-ician can globally assess change from baseline in the patientusing a 7-point scale (1 = marked improvement, 4 = no change,7 = marked decline) [59].

The MMSE and the Global Deterioration Scale (GDS) [60]

were the two secondary outcome measures for cognition anddisease severity, respectively, used by all four Phase III trials.The MMSE evaluates cognition in five areas; orientation,immediate recall, attentional and calculation, delayed recall,and language. The MMSE test scores range from 0 (severeimpairment) to 30 (normal). The MMSE and the ADAS–Cogassess similar domains, and a high correlation between theresults would be expected. GDS is reported as a score from 1to 7, 1 indicating normality, 7 indicating very severe dementia,and is a global assessment carried out by a clinician who hasaccess to all information about a patient.

Cognition & global functionPrimary outcome measures for all Phase III trials were cogni-tion and global functioning as measured by the ADAS–Cogand the CIBIC-Plus, respectively, conducted at baselineand weeks 12, 18 and 26. Statistical power was set to detect dif-ferences of at least 3.0 points or better on ADAS–Cog and aresponder rate of 15–30% on the CIBIC-Plus (calculated to beapproximately 200 patients/group). Adverse effects wererecorded at each scheduled visit (TABLE 1).

Studies showed that the higher dose of rivastigmine(6–12 mg/day, mean dose approximately 10 mg/day) appearedto confer a statistically significant benefit to participants whencompared with placebo, as measured using the ADAS–Cog andCIBIC-Plus scales. There was also evidence of better MMSEscores in the groups treated with 6–12 mg/day rivastigminecompared with placebo. The GDS carried out at 26 weeks wasdichotomized, counting those showing moderately severe,severe or very severe dementia against those showing moderateor mild dementia. In this measure, there were benefits associ-ated with 6–12 mg/day rivastigmine (55% showed the worsecondition compared with 59% placebo) but not with1–4 mg/day rivastigmine [50].

The reported trials suggested that 6–12 mg/day of rivastig-mine improved the cognitive function of patients with mild-to-moderate probable AD treated over a maximum period of26 weeks as measured by the MMSE (range 0–30) by0.8 points and ADAS–Cog (range 0–70) by 2.1 points [50]. At

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lower doses (≤4 mg/day), differences were in the same directionbut were only statistically significant for cognitive function. Ingeneral, these beneficial effects versus placebo were present bythe end of the titration phase at 12 weeks and persisted there-after. Significant differences in the CIBIC-Plus were observedat 26 weeks (with 6–12 mg/day rivastigmine) but not earlier.

In one pivotal study, the magnitude of cognitive benefitdetermined by the change in ADAS–Cog in patients treatedwith 6–12 mg/day rivastigmine versus placebo was relativelylarge compared with reported trials with other ChEIs [47]. Inthis study, there was a particularly rapid mean rate of decline inthe placebo group, a factor that has since been associated withgreater responses to rivastigmine treatment.

Activities of daily livingIn a pooled analysis of three Phase III studies of rivastigmine(6–12 mg/day) in mild-to-moderate AD, clinically and statisti-cally significant improvements were noted for several ADLitems (as measured by a validated ADL scale) compared withplacebo using intention-to-treat analysis [47,48,NOVARTIS PHARMA-

CEUTICALS, UNPUBLISHED DATA]. In these studies, the ProgressiveDeterioration Scale (PDS) was used to evaluate functional disa-bility [61]. In these studies, baseline PDS scores correlated withdisease severity as measured by the GDS (p < 0.001). Placebo-treated patients deteriorated during the 6-month studies; meanPDS change scores were -2.3, -3.3 and -6.3 for the mild, mod-erate and moderately severe groups, respectively. Patientstreated with rivastigmine demonstrated less deterioration, withmean change scores of 0.3, -0.5 and -2.2 for the mild, moderateand moderately severe groups, respectively. Comparisons ofchange-from-baseline scores after 6 months of treatment indi-cated significant beneficial effects with rivastigmine (p < 0.05)versus placebo). The treatment difference was greater forpatients with moderately severe disease than for those with milddisease (4.1 vs. 2.6 points, respectively). All published rand-omized controlled studies to date using rivastigmine haveincluded functional assessment methods only as a secondaryoutcome measure. Secondary outcomes do not affect regulatorydecisions regarding the approvability of ChEIs in the USA.Patients are not selected or randomized on the basis of second-ary outcome measures, differences between placebo and treat-ment groups may exist at baseline, and definitive response ortreatment conclusions cannot be based on theseobservations [62]. There are no published studies to date in ADusing rivastigmine to assess time-to-reach-ADL milestoneapproach using a validated instrument to assess disability.

Behavioral symptomsChEIs have psychotropic properties and may play a role in con-trolling neuropsychiatric and behavioral disturbances in patientswith AD and thus achieving these goals [63]. Preliminary datasuggest that rivastigmine may improve or delay the onset ofneuropsychiatric and behavioral symptoms of AD, especially ifinstituted early in the course of the disease [64]. In a study of34 patients with AD, using the CIBIC-Plus, patients were

Table 1. Primary and secondary end points at 26 weeks of Phase III placebo-controlled studies with rivastigmine in Alzheimer’s disease (intention-to-treat analysis).

Measure Rivastigmine Placebo Ref.

ADAS–Cog: change from baseline

-0.30 1.30 [48]

1.20 2.80 [NOVARTIS PHARMACEUTICALS,

UNPUBLISHED DATA]

1.0 2.40 [NOVARTIS PHARMACEUTICALS,

UNPUBLISHED DATA]

0.30 4.10 [47]

CIBIC-Plus: no change or worse

63.5% 80% [48]

77% 81% [NOVARTIS PHARMACEUTICALS,

UNPUBLISHED DATA]

71.7% 74.5% [NOVARTIS PHARMACEUTICALS,

UNPUBLISHED DATA]

50% 84.8% [47]

PDS: change from baseline

0.00 2.20 [48]

2.70 4.90 [NOVARTIS PHARMACEUTICALS,UNPUBLISHED DATA]


1.50 4.90 [47]

GDS: moderately severe, severe, very severe dementia

36% 42.8% [48]

42.3% 46.8% [NOVARTIS PHARMACEUTICALS,UNPUBLISHED DATA]

62.1% 73.5% [NOVARTIS PHARMACEUTICALS,UNPUBLISHED DATA]

75.7% 75.7% [47]

MMSE: change from baseline

-0.22 0.50 [48]



-0.20 0.90 [47]

ADAS: Alzheimer’s Disease Assessment Scale; CIBIC: Clinician’s Interview-Based Impression of Change; GDS: Global Deterioration Scale; MMSE: Mini-Mental State Examination; PDS: Progressive Deterioration Scale.

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randomized to receive rivastigmine (6–12 mg/day) for 26 weeksor placebo, followed by an open-label extension period.At week 26, a significant improvement was observed in patientswho received rivastigmine (p = 0.02) versus placebo. At weeks 52and 104, mood disturbances had improved significantly frombaseline (p = 0.001). In addition, the mean score for hallucina-tions at week 52 was significantly lower than the baseline score(p = 0.02). Other symptoms (including paranoia, aggressivenessand activity disturbances) remained stable for the 2-year period.Patients who received treatment early on achieved greater benefitthan those whose treatment was delayed for 6 months. Prelimi-nary evidence also suggests that patients with AD treated withrivastigmine have a reduced risk of initiating therapy with anantipsychotic drug compared with patients who receive no ChEItreatment [65]. A recent study with rivastigmine showed that overhalf of 657 community-dwelling patients with mild-to-moderateAD discontinued or decreased (by at least 25%) their use of psy-choactive medications (including antipsychotics) in parallel withboth cognitive and behavioral improvements following initiationof prolonged treatment with rivastigmine [66].

Long-term dataThere are no double-blind, placebo-controlled studies longerthan 6 months assessing the effects of rivastigmine in patientswith AD. Data regarding clinical efficacy beyond 6 months arenot required by regulatory agencies for drug approval. However,in practical terms, long-term efficacy is important in treatingAD. Therefore, many patients who completed the 6-month,double-blind, placebo-controlled trials of rivastigmine enrolledin open-label studies and some have been taking the drug forover 5 years. Open-label and observational studies, and experi-ence with rivastigmine in a real-world setting, appear to showsome benefit in outcomes such as delayed time to nursing homeplacement and caregiver burden. Over a 5-year period, rivastig-mine therapy was safe and well tolerated, with no drop-outs dueto adverse effects past the initial titration period [67]. A recentanalysis assessed MMSE scores in patients with AD whoreceived rivastigmine for up to 5 years [68]. Rivastigmine datacame from two pooled open-label extensions of four 6-month,randomized, placebo-controlled trials. Projections of decline,had the same patient not been treated, were made using a base-line-dependent mathematical model. MMSE data were availablefor 1998 rivastigmine-treated patients and 657, 298 and83 patients were still on treatment at 3, 4 and 5 years, respec-tively. The mean baseline MMSE score was 19.3 (SD 4.9). Pro-jected mean scores in model-based untreated patients declinedbelow 10 points on the MMSE at about 3 years, while the meanMMSE score of patients who remained on rivastigmine stayedabove 10 points for 5 years. Rivastigmine appears to show a par-ticularly favorable profile during maintenance therapy. It islikely that specific pharmacologic characteristics, including dualand sustained AChE and BuChE inhibition, brain versusperipheral and brain region selectivity, and CYP-independentmetabolism may contribute to the good safety, tolerability andefficacy profiles observed with this agent in clinical practice.

Advanced Alzheimer’s diseasePreliminary data show that rivastigmine may have cognitiveand functional benefits, especially in severe AD [69,70]. A meta-analysis of AD patients with the greatest cognitive impairment(MMSE scores between 10 and 12) enrolled in three rand-omized, double-blind, placebo-controlled, 6-month trialsfound that cognitive function improved slightly relative tobaseline (0.2 points) in patients after 26 weeks of treatmentwith rivastigmine (average dose 9 mg/day), as measured by theADAS–Cog [72]. Patients in the placebo group had a meandecline of 6.3 points. MMSE after 26 weeks in the rivastigminegroup declined 0.8 points compared with 2.5 points in the pla-cebo group. Performance of activities of daily living in therivastigmine group declined 2.0 points on a 6-item score whilemean decline among placebo patients was 6.3 points(p = 0.065) using an intent-to-treat analysis. Patients treatedwith rivastigmine showed a statistically significant reduction inaggressiveness after 26 weeks (p = 0.023) in observedtreatment cases.

Nursing home populationApproximately three-quarters of the more than 1.5 millionnursing home residents in the USA suffer from dementia.Open-label study results and large meta-analyses suggestedthat treatment with rivastigmine may have beneficial cogni-tive and behavioral effects (including mood, aggressiveness,activity disturbances, paranoid features and hallucinations)in persons with dementia living in the community or innursing homes [71,72]. Beneficial effects of rivastigmine onbehavioral symptoms in nursing home residents with ADwere sustained for up to 12 months, with 50% of patientsexperiencing improvements of 30% in overall neuropsychiat-ric inventory – nursing home version (NPI–NH) score [73,74].A recent small study in which 26 patients received double-blind rivastigmine showed no benefits in the treatment ofagitation in people with dementia in institutional care [75].Another recent open-label study showed that treatment withrivastigmine was associated with a reduction in the self-reported professional caregiver burden in nursing homeresidents with AD [76].

Predictors of responseAlthough there are no reliable methods of predicting whichpatients will gain most from these drugs, preliminary data sug-gest some predictors of response to rivastigmine therapy, suchas hallucinations, attentional deficits, naturally more rapidlyprogressive AD, presence of vascular risk factors, presence ofDLB pathology with AD, severity of dementia, higher baselineADAS–Cog score and EEG slow-wave activity [77–80]. Medialtemporal lobe atrophy may not be a clinically useful predictorof cognitive response in subjects with probable AD who aretreated with rivastigmine [81]. There is conflicting data concern-ing the apolipoprotein E (APOE) genotype, with one studyfinding no benefit of this genotype as a predictor of cognitiveresponse with rivastigmine in patients with AD [81], whereas

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another found that APOE ε4 patients with AD showed agreater cognitive response compared with placebo-treatedpatients with AD [82].

Disease-modifying effects of rivastigmineNo clear data are available regarding the disease-modifyingeffects of any ChEI. Accumulating evidence points to animportant role of intraneuronal Aβ peptide as a trigger of thepathologic cascade of events leading to neurodegeneration andeventually to AD [83]. Recent evidence from preclinical studiesindicates that ChEIs can attenuate neuronal damage and deathfrom cytotoxic insults, and therefore may affect AD pathogen-esis [84]. The mechanisms by which these actions are mediatedmay or may not be directly related to their primary mode ofaction. Some researchers have proposed that the influence ofcholinergic stimulation on amyloid formation is critical inlight of the early targeting of the cholinergic basal forebrain inAD and the possibility that maintenance of this cholinergictone may slow amyloid deposition [85]. Both AChE andBuChE are associated with the formation of amyloid plaquesand NFTs. Advanced plaque formation shows as much as 87%BuChE activity and 80% AChE activity, which has been dem-onstrated to accelerate the formation of Aβ. In this context,the dual action of certain ChEIs on their ability to increaseACh levels and decrease amyloid burden assumes significanceas it may identify a single drug to both arrest the progressionof the disease as well as treat its symptoms. A recent studyfound donepezil to be associated with a decreased rate of hip-pocampal atrophy in patients with AD compared with historiccontrols [86]. The authors of this study suggest that this effectmay be linked to the effects of AChE on Aβ metabolism.Potential long-term effects of rivastigmine on disease progres-sion may also be linked to drug effects on vascular changes inAD [87]. A study showing less-severe worsening of cognitionafter withdrawal of rivastigmine treatment in patientspreviously treated with rivastigmine compared with placebosuggests an effect on disease progression [88].

Comparative studies in Alzheimer’s diseaseAlthough ChEIs share a common mechanism of action, it isknown that the drugs differ pharmacologically. These differ-ences can significantly affect the safety, tolerability and efficacyprofiles of each drug and may ultimately determine the successof treatment. There is uncertainty about which of the fouravailable ChEIs should be prescribed as initial therapy forpatients with AD. Considerable methodologic limitations ofpublished studies comparing two cholinesterase inhibitorsreduce any confidence in the validity of the conclusionsdrawn [89]. Newly treated AD patients in a usual care settingwho initiate therapy with either rivastigmine or donepezil havesimilar levels of persistency with treatment [90].

Switching from another cholinesterase inhibitorCurrently, all ChEIs are classed together as a group, although itwould appear that they have different modes of action. This

creates the opportunity to switch within the class shouldefficacy or tolerability be an issue. A number of open-labelstudies in which patients were switched from donepezil torivastigmine, have indicated that approximately 50% ofpatients experiencing lack/loss of efficacy with donepezilrespond to subsequent treatment with rivastigmine [91,92]. Inthese studies, rivastigmine was well tolerated, and the occur-rence of safety/tolerability problems with donepezil was notpredictive of similar problems with rivastigmine. A more recentstudy suggests that transitioning patients from donepezil torivastigmine without a washout period is well tolerated andappears to have a favorable safety profile [93]. These data suggestthat patients not tolerating or not responding to donepezil orgalantamine may still draw benefits upon switching torivastigmine and vice versa [94].

Other dementiasPure AD only accounts for approximately 55% of autopsy-con-firmed cases of dementia [10]. Mixed dementias (AD withanother pathology such as vascular dementia [VaD], DLB orPDD) account for up to 25–33% of dementia cases [95,96].There is increasing evidence that the ChEIs target changes latein the pathologic process (i.e., on the final common pathway ofthe pathologies of the different types of dementia, rather thanspecifically in AD). Cerebrovascular disease (CVD), as well assecondary ischemic brain injury from cardiovascular disease, arecommon causes of dementia and cognitive decline in the eld-erly [97]. In addition, CVD frequently contributes to cognitiveloss in patients with AD and often converts patients with pre-clinical AD to clinical AD [9]. Preliminary data with rivastig-mine in VaD, as well as in patients with AD plus CVD, havedemonstrated improvements in cognition, behavior andADL [98–104]. The term vascular cognitive impairment (VCI)has been used to describe people with cognitive problems dueto cerebrovascular disease that do not meet the criteria fordementia. From existing trial data, there is some evidence ofbenefit of rivastigmine in VCI [105]. Large, randomized, double-blind, placebo-controlled studies are needed to confirm thebenefits of rivastigmine for patients with vascular dementiaand VCI.

DLB is the second most common cause of neurodegenerativedementia in older people [106]. There is good evidence of wide-spread cholinergic losses even in early stages of DLB, and thischolinergic deficit is even more severe than AD [107]. Onedouble-blind, placebo-controlled study of 120 patients withDLB showed that rivastigmine-treated patients demonstratedstatistically significant improvements in behavioral symptomsusing the NPI [108] following 20 weeks of treatment, comparedwith placebo-treated patients [52]. The behaviors most respon-sive to rivastigmine were apathy, hallucinations, delusions, anx-iety and agitation. Marked neuroleptic sensitivity in DLB alsomakes the importance of this treatment effect a welcomeone [106]. Although not found in the double-blind, placebo-controlled study, rivastigmine was found to be beneficial forcognitive (especially attentional) symptoms of DLB in two

Rivastigmine


other open-label trials [52,106,109]. Moreover, the benefits ofrivastigmine in DLB patients have been shown to persist forup to 96 weeks [53]. Hallucinations predict attentionalimprovements with rivastigmine in DLB [110].

Dementia is common among patients with Parkinson’sdisease, with the prevalence approaching 80% over the longterm [111]. In a recent placebo-controlled study including451 patients with PDD, rivastigmine was associatedwith moderate cognitive, functional and behavioralimprovements [54].

As in AD, rivastigmine was associated with nausea and vom-iting in patients with VaD, LBD and PDD, although there wasa tendency for the rates of these events to be slightly lower thanin pivotal AD trials, possibly reflecting greater cholinergic defi-cits, desensitization of dopamine D2 receptors in the area pos-trema (the putative vomiting center of the brain) or the slowerdose-escalation schemes used in some of these studies. In thePDD and LBD studies, rivastigmine was associated withincreased tremor, but not with any more serious extrapyramidaladverse events.

In an open-label study, rivastigmine-treated patients withfrontotemporal dementia were less behaviorally impaired andcaregiver burden was reduced, at 12 months, compared withbaseline [112]. Rivastigmine may also be beneficial in the man-agement of dementia in adults with Down’s syndrome [113].Additionally, in a prospective, open-label, randomized, control-led study, rivastigmine had a modest beneficial effect on motorand cognitive impairment in subjects with Huntington’sdisease [114].

Mild cognitive impairmentUnpublished reports state that rivastigmine was not statisticallysignificantly better than placebo in primary efficacy end pointsin subjects with MCI [GT GROSSBERG MD, INDEPENDENT INVESTI-

GATOR PERS. COMMUN.]. However, some of the secondary efficacymeasures did reach statistical significance versus placebo inMCI subjects. Also, APOE ε4 positive patients with AD had arobust response to drug compared with placebo in subjectswith MCI.

Other conditionsPreliminary data using rivastigmine suggest potential benefitsin cognitive function for a wide variety of disorders, such asmultiple sclerosis, prevention of delirium in hospitalizeddementia patients, schizophrenia and autistic disorders [115–119].

Health economicsTotal annual costs of caring for patients with AD in the com-munity are high [7]. Most of the financial burden was borne bythe patients with AD and their families. In this light, cost bene-fits of any antidementia drugs become very important. Prelimi-nary data suggest that treatment with rivastigmine maydecrease cost of care and time spent in caregiving for families ofpatients with AD [120]. There are no published specificcost–effectiveness studies of rivastigmine (or any other ChEI)

which prospectively collected empirical data on cost and out-comes [121]. There are no published randomized clinical trialsusing ChEI with such empirical data with a cost consequenceanalysis design, indicating cost benefit, loss or neutrality. Earlyand reliable prediction of treatment response with rivastigmine(as with other ChEIs) may allow a more effective and thuseconomic use of rivastigmine in patients with AD.

DosingRivastigmine is a white to off-white, fine crystalline powderthat is soluble in water and alcohol. The commercial drug isavailable as 1.5, 3.0, 4.5 and 6.0 mg capsules. In AD, the sug-gested dosage range for rivastigmine is 6–12 mg/day. Evidencefrom the clinical trials shows that doses at the higher end(9–12 mg/day) may be more beneficial [31]. Patients can begintherapy with 1.5 mg twice daily (morning and evening) andgradually increase (every 4 weeks) to the maximum dosage of6.0 mg twice daily. It should be administered with food tomaximize tolerability and absorption. In patients experiencingGI events during the titration phase, a slower titration may bepreferable at the physician’s discretion. If GI side effects occur,dose can be decreased to the former level and no further effortis needed to increase the dose in case this dose is at least6 mg/day. In DLB, if insomnia is due to hallucinations, therivastigmine dose can be administered three-times daily withthe last dose with some food at 2200 hours. A liquid solutionformulation (2 mg/ml) of the drug is now available, and apatch formulation is under development. Both formulationshave the same dosing and titration schedule. It is recommendedthat patients should receive the highest tolerated dosage.

ConclusionsClinical evidence supporting ChE inhibition as the mechanismby which rivastigmine (as well as other ChEIs) treat thesymptoms of AD is accumulating. Although Wilkinson said inhis review article that he does not believe that the evidence avail-able to date demonstrates the clinical significance of inhibitingBuChE [124], many experts (including the present authors) say itis a contributor and an important target in the treatment of AD.

The findings of randomized, double-blind, placebo-controlled,6-month studies demonstrated that rivastigmine at higher doses(6–12 mg/day) was superior to placebo on measures of globaland cognitive function in patients with mild-to-moderatelysevere AD. It may also slow functional decline, as shown usingscales for ADL that were used as secondary outcome measures inthese trials. Tolerance to the therapeutic effects of rivastigminedoes not occur. Behavioral change was not one of the principaloutcome measures in the original Phase III rivastigmine trials inpatients with mild-to-moderate-stage AD, although meta-analyses and open-label studies have suggested behavioral bene-fits in these patients. Most of the patients in the pivotal studieshad concomitant disorders that were being treated with numer-ous other drugs. In addition to AD, rivastigmine is the onlyChEI to have also demonstrated clear efficacy in DLB and PDDin large, double-blind, placebo-controlled trials.

Desai & Grossberg


Rivastigmine is generally well tolerated with no requirementfor routine electrocardiogram or blood monitoring. Rivastigminecauses centrally mediated adverse events that are typical of thoseexpected from a ChEI and mainly involve GI events. They areusually mild to moderate, of short duration and responsive todosage reduction. They occur mostly during the dosage titrationphase and appear to resolve spontaneously with continued use,thus decreasing in frequency during the maintenance phase.Although GI side effects (especially nausea and vomiting) wereobserved in more than 30% of patients in the trials, these ratesinclude data from trials that employed forced titration (up-titra-tion once a week), which is not recommended for this drug. It isrecommended that rivastigmine be taken with food and that thedoses should be escalated slowly in at least 4-weekly intervals.

A common pattern of response to treatment is initial improve-ment in cognition, followed by maintenance of cognitive gainsabove baseline for up to 1 year. Generally, there is a decline incognition to below baseline levels after approximately 1 year oftreatment, but the level of cognition remains above thatpredicted for those not receiving pharmacologic treatment [123].

Limitations of current researchAll pivotal trials involving antidementia drugs have used boththe ADAS–Cog and the CIBIC-Plus or a similar measure toassess global outcome. None of the pivotal studies assessed theeffects of treatment on other important outcome measures(e.g., ADL, behavior or patient and caregiver satisfaction) asprimary outcome measures. ADAS–Cog has certain disadvan-tages in that it is not widely used outside clinical trials, so judg-ment of its aptness is difficult. In addition, as a psychometricmeasure, it cannot capture any important qualitative differ-ences that sometimes arise in patients taking the test. As such,ADAS–Cog is poorly suited to discovering the effects of ADthat are not among the symptoms regularly screened for [124].Yet it is the gold-standard measure of cognition and the onethat the US Food and Drug Administration specifies should beused in AD studies. This is why all ChEI trials used it as theprimary efficacy measure. Also, ADAS–Cog is strongly relatedto the MMSE, often used in memory clinics. Even with theCIBIC-Plus, clinicians are constrained in observing onlyknown effects of disease and treatment, in that the scale appearsto be better at the recording of worsening (which is well under-stood) than improvement (which is not) [125]. The ADAS–Cogand the CIBIC-Plus scores may not be sufficient tools for theassessment of treatment success. Finally, the placebo-controlledtrials are not that blind, with 30% easy-to-detect side effects.

Since many of the outcomes in AD are influenced by theinteraction of complex genetic, social and environmental fac-tors and medical comorbidity, they may be inappropriate forassessing the neuroprotective effects of rivastigmine, or for thatmatter, any other ChEI.

Expert commentaryAlthough all ChEIs (including rivastigmine) have been shownto benefit cognition and global function in patients with

mild-to-moderate AD, it is not universally agreed that thesechanges translate into positive outcomes such as maintenanceof ADL, reduced caregiver burden and delayed nursing homeplacement [126,127]. The recent Expert Consensus Guidelines forthe treatment of dementia recommends a ChEI to slow cogni-tive impairment in mild-to-moderate AD and combining aChEI with a NMDA antagonist (e.g., memantine) if a patientwith mild-to-moderate dementia has an inadequate response tomonotherapy [46].

The authors agree with the expert consensus. Rivastigmine isrecommended for the treatment of mild-to-moderate AD forslowing cognitive decline and the decline in global functioning.It may also benefit ADL, behavioral disturbances and caregiverburden. The modest effect observed is equivalent to preventinga 2–3 month/year decline in a typical patient with AD. Long-term treatment studies with rivastigmine in AD subjects haveshown delays in decline of about 2 years compared with theprojected decline of AD subjects on placebo. Rivastigmine usemay extend to more advanced stages, to mixed dementias (ADwith VaD or DLB), other dementias (especially DLB andPDD) and to AD with CVD. Rivastigmine treatment maydecrease the risk of nursing home placement for people withAD [128]. Thus, early diagnosis and treatment of AD withrivastigmine is crucial to successful outcomes [123], especially ifhypotheses concerning the effects on disease progressionhold true.

In patients with moderate-to-severe AD, adding rivastigmineto a NMDA receptor antagonist such as memantine is anappropriate strategy [46], especially for patients having inade-quate response even to rivastigmine after switching from anAChE-selective inhibitor. Memantine does not interfere withthe cholinesterase inhibition by rivastigmine in vitro orin vivo [129]. Also, postmarketing surveillance reports thatexamined the coadministration of memantine with ChEIs(including rivastigmine) in clinics in Germany indicated thatno serious adverse reactions were reported.

With regard to the three different domains of cognition, glo-bal functioning and function in ADLs, individual patients haveshown variability in how they responded to treatment withrivastigmine and other ChEIs. Significant benefits in cognitivefunction do not necessarily correlate with improvements in glo-bal functioning or with functioning in ADLs. Thus, clinically itis important to assess response to ChEIs in several domains(cognition, function in ADLS, global function and behavior) inany future trials in any dementia types. In pooled data frompivotal rivastigmine trials in AD, 55% of patients had stabiliza-tion or improvement in these individual domains but, overall,86% had a beneficial response in one or more domains.

The benefits of rivastigmine (as well as other ChEIs) in treat-ing cognitive and noncognitive symptoms associated with ADare not sustained indefinitely, and the illness continues toprogress even while patients are receiving treatment [130].However, patients are believed to deteriorate later, or moreslowly, under treatment than if they are left untreated [131].Therefore, long-term treatment is an important treatment goal.

Rivastigmine


However, it is important to manage caregiver and patientexpectations as it is unlikely that marked improvements will besustained. In cases of treatment failure, it is usually worthwhileto consider other management and pharmacologic strategies,such as switching to another agent in the same class, or addinga NMDA receptor antagonist [132]. Combining two ChEIs isnot recommended.

Patients with AD deserve to receive the optimum benefitfrom ChEI treatment, which can only be achieved through thediligent and appropriate use of concurrent pharmacotherapy(especially minimizing the use of anticholinergic drugs).Caregivers and patients must have realistic expectations; drugeffects are modest and sometimes no symptomatic improve-ment is noted. In fact, a report of no change means that thesedrugs are helping as without ChEIs one would have observed adecline in functioning.

Once therapy with rivastigmine is begun, patients should beevaluated in the first month for medication tolerability, butshould wait 3–6 months to evaluate the need for continuingtreatment. Patient and caregiver reports, clinical cognitive andfunctional assessments should be used to determine the needfor continuing medication treatment. Because AD is a progres-sive disease, no change or mild improvement in cognitive orADL functioning after 6 months is an indication for continu-ing treatment with rivastigmine. For how long to expect a sus-tained response to a ChEI is unclear. Many patients may showno change for a year and then start showing gradual decline.Rivastigmine should be restarted at the same low dose (1.5 mgtwice-daily) and gradually increased if, for any reason, it wasdiscontinued for longer than 3 days.

Rivastigmine may be considered one of the drugs of firstchoice for the treatment of mild-to-moderate AD. Patients whohave been on tacrine or donepezil and failed (intolerable sideeffects or accelerated decline) should be considered for a trial ofrivastigmine. Patients with AD who are doing well on otherChEIs should not be changed over to rivastigmine.

The most common side effects are GI, which frequentlyimprove with continued use. If unacceptable side effects occurat higher doses, the dose should be decreased. Rivastigmineshould be discontinued in the case of noncompliance, if sideeffects persist at the lowest dose, if the patient continues todecline significantly after a 6-month trial or if a medicalcondition develops that is a contraindication to continuedrivastigmine therapy.

For residents with dementia in long-term care, despite thenegative study involving the nursing home population, ChEIsuch as rivastigmine may offer modest benefit to some patientsin outcomes more specific to long-term care residents such ashospital admissions, falls, decubitus ulcers, weight loss, use ofphysical and chemical restraints, staff turnover, and use of psy-chotropics. Amongst ChEIs, rivastigmine has the most consist-ent clinical efficacy in terms of improving behavioral outcomesin both AD and other dementia types [133]. Having said this,rivastigmine or any other ChEI should be used with extracaution in nursing home populations due to the considerable

frailty observed in this population. On the other hand, ChEIssuch as rivastigmine may be safer than atypical antipsychoticsin managing mild-to-moderate chronic behavioral disturbancesin nursing home residents with dementia [133]. This isimportant due to the recent warnings of an increased risk ofstrokes and mortality associated with use of atypicalantipsychotics [201,202]. Antispasmodics, anticholinergics andpropulsive agents were more likely to cause adverse events andrequire treatment in patients receiving rivastigmine than inthose receiving placebo [45]. The combination of rivastigmineand diuretics was associated with severe adverse effects andbody weight loss. Salicylate and rivastigmine combinationswere associated with body weight loss and malaise [45].

Five-year viewThere are no novel ChEIs in sufficiently advanced stages ofclinical development to anticipate fundamental changes in theChEI marketplace over the next 5 years. Although future dis-ease-specific and possibly preventive treatments for AD mayeventually eliminate the need for symptomatic agents likeChEIs and NMDA receptor antagonists, these are not suffi-ciently developed to have a substantial impact in the next5 years. Thus, rivastigmine, along with other ChEIs, is likely toremain an important treatment for AD over the next 5 years. Avariety of studies will be conducted and published, clarifyingthe role of rivastigmine in AD and related disorders, alone andin combination strategies (BOX 1). The results of a large,ongoing, head-to-head study (EXCEED [Exelon Comparisonof Efficacy versus Donepezil]), assessing the safety, tolerabilityand efficacy of rivastigmine and donepezil over 2 years willprovide direct evidence of the comparative long-term effects of

Box 1. Possible studies involving rivastigmine in Alzheimer’s disease and related disorders over the next 5 years.

• Combination of rivastigmine and N-methyl-D-aspartate receptor antagonist such as memantin.

• Comparison of donepezil and rivastigmine for the treatment of Alzheimer’s disease over the long term (>2 years; EXCEED [Exelon Comparison of Efficacy versus Donepezil] study).

• Rivastigmine in patients with mild cognitive impairment.

• Rivastigmine in combination with disease-modifying agents (e.g., Alzhemed™, Neurochem Inc.).

• Studies with rivastigmine that include delay in reaching activities of daily life-related clinical milestones, as well as functional assessments as primary outcome measures to further clarify the role of rivastigmine in optimizing quality of life

• Studies to prospectively assess economic and disease-specific outcomes over long periods (> 2 years) to clarify cost–effectiveness and other benefits of rivastigmine therapy

• Studies to clarify predictors of response to rivastigmine

Desai & Grossberg


donepezil and rivastigmine. The long-term benefits ofrivastigmine starting in predementia AD and remainingthrough to advanced AD may be considerable. Noncognitivemeasures, such as evaluating changes in ADL, behavior, car-egiver burden, quality of life and resource use, need to be pri-mary outcome measures to better clarify the clinical effective-ness of rivastigmine and other ChEIs for people with AD.Current practice, in dementia and elsewhere, does not includepatient preferences and misses out on the opportunity to sys-tematically record genuine effects of treatment [124]. Patient andcaregiver satisfaction need to be incorporated into our assess-ments of drugs for the treatment of AD and related disorders.For patients with AD, prolonged use of placebo is not possibleon ethical grounds and add-on designs are now favored (thedrug potentially modifying progression of AD or a placebo isadded to a stable therapeutic dose of a ChEI for at least 1 year,

with the option of a double-blind wash-out of the experimentaldrug for up to 3 months in order to establish if differencesbetween the treatment groups at the end of the year disappearon wash-out, which would suggest a reversible symptomaticbenefit) [134]. The current licensing, which restricts the use ofrivastigmine to mild-to-moderate AD sufferers, is likely to beextended to cover other forms of dementia as more dataemerges. A greater understanding of BuChE, its effect on amy-loid formation and the role of neurotransmiters may result instudies with rivastigmine and other ChEIs that inhibit BuChEto assess whether they can alter the course of the disease as wellas having symptomatic effects. With other conditions, such asschizophrenia, showing cholinergic receptor abnormalitiesrivastigmine will be studied in a wider range of disorders thaninitially imagined. The patch formulation of rivastigmine maybecome available within the next 5 years.

Key issues

• Rivastigmine is a novel acetylcholinesterase and butyrylcholinesterase inhibitor that is indicated for the treatment of mild-to-moderate Alzheimer’s disease.

• Multiple clinical trials indicate improvements in cognitive test scores and global outcomes relative to placebo among rivastigmine-treated patients with Alzheimer’s disease.

• Among the members of the cholinesterase inhibitor class, rivastigmine has the most rigorous data showing efficacy for behavioral and cognitive symptoms in patients with dementia with Lewy bodies and for cognitive symptoms in patients with Parkinson’s disease dementia.

• Rivastigmine is generally well tolerated if taken on a full meal and up-titrated at 4-week intervals.

• Unlike other members of the cholinesterase inhibitor class, rivastigmine does not require the cytochrome P450 liver enzyme system for its metabolism and thus is the least likely to be associated with clinically significant pharmacokinetic drug–drug interactions.

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120 Marin D, Amaya K, Casciano R et al. Impact of rivastigmine on costs and on time spent in caregiving for families of patients with Alzheimer’s disease. Int. Psychogeriatr. 15(4), 385–398 (2003).

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127 Lanctot KL, Herrmann N, Yau KK et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer’s disease: a meta-analysis. CMAJ 169(6), 557–564 (2003).

128 Beusterien KM, Thomas SK, Gause D et al. Impact of rivastigmine use on the risk of nursing home placement in a US sample. CNS Drugs 18(15), 1143–1148 (2004).

129 Enz A, Gentsch C. Co-administration of memantine has no effect on the in vitro or in vivo determined acetylcholinesterase inhibition of rivastigmine in the rat brain. Neuropharmacology 47(3), 408–413 (2004).

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Websites

201 US Food and Drug Administration, Center for Drug Evaluation and Research. Atypical antipsychotic drugs information. www.fda.gov/cder/drug/infopage/antipsychotics/default.htm (Accessed August 2005)

202 Committee on the Safety of Medicines (CSM). Atypical antipsychotic drugs and stroke: message from Professor Gordon Duff, Chairman, Committee on Safety of Medicines. Available at CSM website 2004www.mca.gov.uk/aboutagency/regframework/csm/csmhome.htm (Accessed August 2005)

Affiliations

• Abhilash K Desai, MD

Medical Director, Alzheimer’s Center of Excellence, ThedaCare Behavioral Health & Clinical Instructor, Saint Louis University School of Medicine, 3211 E Northshore Boulavard, #157, Appleton, WI 54915, USATel.: +1 920 720 3870Fax: +1 902 720 [email protected]

• George T Grossberg, MD

Samuel F Fordyce ProfessorDirector of Geriatric Psychiatry, Saint Louis University School of Medicine, 1221 S Grand Boulavard, Saint Louis, MO 63104, USATel.: +1 314 577 8721Fax: +1 314 268 5490

rivastigmine for alzheimer’s disease

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