A review of rivastigmine: A reversible cholinesterase inhibitor

New Drugs A Review of Rivastigmine: Cholinesterase Inhibitor

A Reversible

Bradley R. Williams, PharmD, L2 Arlette Nazarians, Mark A. Giii, YharmDl Departments of IPharmacy and 2Gerontology, Pharmacy, Los Angeles, Calqornia

University

of Southern

PharmD,l Calqornia

and

School of

ABSTRACT

Background: Rivastigmine tartrate is a reversible cholinesterase inhibitor indicated for the symptomatic treatment of mild to moderate dementia. It was approved by the US Food and Drug Administration for the treatment of Alzheimer’s J;rnnr,, \LuJ, /An\ fin An&l 71 -InCJCl u13La3L “II LxpJLU LI, L”““. Objective: The purpose of this review was to summarize the background on dementia of the Alzheimer type and the pharmacokinetic properties, efficacy and tolerability profiles, clinical applications, adverse effects (AEs), drug interactions, and pharmacoeconomics of rivastigmine. Methods: A literature search was conducted using MEDLINE (199%2002), EMBASE Geriatrics and Gerontology (199%2002), the National Institutes of Health Alzheimer’s Disease Education and Resource Center Combined Health Information Database, and Google. Search terms included rivastigmine, Exebn, EAJA713, and EAJA-713. The bibliographies of retrieved articles also were searched for relevant articles. R~cmltc* I\c..JUIC.J.Tn 111clinic-al LIIIIILc(I trialc LIXAL.,,rixractinminp II Y“dL’b”““L

hat ILLAdimnmmvl ““y”” YLU nr “I maintain4 IIIL*IIILC(IIILUrnnnitixrp LV5LUL’YL

function, global function (ie, activities of daily living [ADLs]), and behavior in patients with mild to moderate AD for up to 52 weeks. AEs are generally mild to moderate and primarily affect the gastrointestinal (GI) tract. Clinically significant drug interactions with rivastigmine have thus far not been reported. Treatment with rivastigmine for up to 2 years may reduce the cost of caring for patients with AD. Cost savings are minimal during the first year, particularly for those with mild disease, hut increase during the second year of treatment. Cost savings Awsptedfor Printed

1634

pubkation

April 3, 2003.

in the USA. Reproduction

in whole

0 149-29 l8/03/$l9.00

or part is not permitted.

Copyright

0

2003

Excerpta

Medica,

Inc.

B.R. Williams

et al.

occur earlier for those with moderate AD. Most savings are realized from a delay in the need for institutionalization. Conclusions: Rivastigmine has been shown to improve or maintain patients’ performance in 3 major domains: cognitive function, global function (ADLs), and behavior. The efficacy and tolerability of rivastigmine have been proved by numerous clinical trials, with the most prominent AE being GI irritation. (Chin Tnev: 2003;25:1634-1653) Copyright 0 2003 Excerpta Medica, Inc. Key words: rivastigmine, Exelon, ENA 713, ENA-713, dementia, Alzheimer’s disease.

INTRODUCTION

The prevalence of dementia ranges from 3.5% to 16.1% for persons aged 265 years, and the syndrome currently affects -2.3 million people in the United States.l The prevalence increases exponentially with age, ranging from 3.0% in patients aged 65 to 74 years to as much as 47.2% for those aged 285 years.2,3 The incidence of dementia also increases with age, and women have a slightly higher risk than men.+ For people aged 265 years, the incidence of dementia in the United States is -14 new cases per 1000 person-years per year, rising to >56 new cases per 1000 person-years per year for those aged 290 years.5 Dementia causes short- and long-term memory impairment and multiple cognitive deficits that compromise social or occupational functioning.6 Dementia is characterized primarily by a gradual onset of progressive symptoms, including difficulty learning or retaining information, inability to handle complex tasks, impaired spatial orientation and abilities, language deficits, and behavioral changes.7 The Diagnostic and Statistical Manual of Mental Disorders, Foutih Edition (DSM-IV)’ diagnostic criteria for dementia require a patient to have (1) memory impairment; (2) at least one of the following: aphasia (language difficulties), apraxia (diminished ability to perform motor activities in the presence of intact motor function), agnosia (inability to recognize or name objects despite intact sensory function), or disturbance in executive function (diminished ability to plan or organize); and (3) impaired social or occupational function.s These impairments must occur in the absence of other disorders that could cause similar signs and symptoms. The purpose of this review was to summarize the background on dementia of the Alzheimer type as well as the pharmacokinetic and pharmacodynamic properties, efficacy and tolerability profiles, clinical applications, adverse effects (AEs), drug interactions, and pharmacoeconomics of rivastigmine. ALZHEIMER’S

DISEASE

Alzheimer’s disease (AD) is the most common cause of progressive mental deterioration in persons aged >65 years; it decreases cognitive function and eventu1635

CLINICALTHERAPEUTIC?

ally causes death, typically from bronchitis or pneumonia.7 AD is characterized by multiple cognitive deficits that progress over time and often are accompanied by behavioral disturbances such as aggression, depression, and wandering.9,10 After diagnosis, many people may expect to live 7 to 10 years with the disease. l1 Etiology

Although a definitive cause has not yet been determined, several have been proposed.6 A genetic role is significant in the development of AD, yet mutations account for ~5% of all such cases. Mutations in the amyloid precursor protein (APP) gene (chromosome 21), the presenilin 1 gene (chromosome 14), and the presenilin 2 gene (chromosome 1) produce an autosomal dominant pattern of inheritance. Because of overproduction or transcription errors, an ahnormal subunit of APP (beta-amyloid) is produced. 12,13The accumulation of beta-amyloid initiates the contributing cell death, disruption of cell membranes, inflammatory response, neurofihrillary tangle (NFT) formation, cerebral amyloid angiopathy, and neurofihrillary degeneration. 12,13 Apolipoprotein (ape) E, a normal protein involved in the metabolism of cholesterol and lipoprotein, has been linked to the development of AD.13 Apo E possesses 3 alleles: r2, ~3, and ~4. Of those alleles, ~4 appears to significantly reduce brain cholinergic activity and increase the risk of AD. l3 Most AD cases occur with advancing age, although family history remains a predisposing factor.13 Neuropathology

Although not a diagnostic symptom, brain atrophy is the most obvious clinical finding in AD.6 The atrophic changes are found primarily in the temporal, parietal, and frontal sections of the brain. l5 Current criteria for the pathologic diagnosis of AD require the presence of both neuritic plaques and NFTs, which correlate with neuron and synapse loss. Neuritic plaques consist of a central core of amyloid protein, often containing paired helical filaments. l3 NFTs contain paired helical filaments of abnormally phosphorylated tau protein that occupy the cell body and extend into the dendrites. The damage caused by plaques, NFTs, and subsequent cell death leads to significantly reduced cholinergic activity in the hrain.13J5 CHOLINERGIC

HYPOTHESIS

Acetylcholine (ACh) is the primary neurotransmitter that facilitates learning and increases attention (Figures 1 and 2). l&l7 The ACh deficiency seen in AD led to the formulation of the cholinergic hypothesis, which states that the inability to transmit neurologic impulses across brain synapses is the cause of cognitive, global, and behavioral dysfunction associated with dementia.15 Three major principles underlie the use of cholinergic agents to treat AD. The first is reduced activity of choline acetyltransferase (ChAT) in the cerebral cortex.15 Lev1636

B.R. Williams et al.

Cortical Figure

I.

Schematic

diagram

Alzheimer’s

of a neuron

disease. (I)

representing

Substantial

for the synthesis of acetylcholine choline,

choline

synaptic

cleft is decreased.

of tau protein

receptors

(5) The

precursor AP

protein

protein.

Adapted

AChE

with

(sAPPa).

the altered deficits

neurotransmission

in the enzyme

from acetyl coenzyme therefore,

release

coupling

of second

(mAChR).

(3) D ecreased

causing

ACh

state receptor

decreased

(6) Th e interaction

= acetylcholinesterase;

APP

of ACh

(nAChR) secretion

into the to

causing a shift

to neurofibrillary with

beta-amyloid

of soluble

also increases = amyloid

and

messengers

coupling

(precursor

in

responsible

A (AcCoA)

(ChAT);

of nicotinic

interaction

Neuron

(2) Decreased

to the hyperphosphorylated

tangles). (4) Interaction (Ap).17

(ACh)

acetyltransferase

the muscarinicACh

cortical

Pyramidal

amyloid

production

precursor

of

protein.

permission.‘0

els of ChAT depletion correlate with the extent of neuritic plaque formation. Second, a reduction occurs in presynaptic muscarinic type 1 and nicotinic receptors, hut postsynaptic muscarinic type 2 receptors are preserved. Third, the large neurons responsible for the supply of ACh to the cerebral cortex, important for attention and new learning, are lost. Neuropathologic studies have shown the presence of NFTs in these neurons. 15,16In addition, cholinergic agonists have been found to facilitate the learning process, which also supports the important role of ACh in attention and learning. Among the different types of drugs that are used to modify cholinergic neurotransmission, only the cholinesterase (ChE) inhibitors have been effective to date.16 One such agent, rivastigmine, is a unique ChE inhibitor that has been approved by the US Food and Drug Administration for the treatment of mild to moderate AD.l’ 1637

CLINICALTHERAPEUTICS@

Choline

-

mAChR Cortical

Figure 2.

The

proposed

(I) Acetylcholine AChE

inhibitors

secretion

neurotransmission (ACh)

of soluble

with

breakdown

(AChEINH).

production

nAChR

= nicotinic

mAChR

= muscarinic ACh

Neuron

acetylcholinesterase

by AChE

is inhibited

(2) R e d uced phosphorylation

amyloid

(4) The

Pyramidal

precursor

of beta-amyloid acetylcholine

protein (Ap)

receptor;

receptor.

Adapted

(sAPPa)

protein APP

(AChE)

inhibitors.

because of addition

of

of tau protein. (3) The returning

is reduced

= amyloid

to normal.

to normal.‘0,‘6

precursor

protein;

with permission.‘o

METHODS

A literature search was conducted using MEDLINE (199%2002), EMBASE Geriatrics and Gerontology (199%2002), Alzheimer’s Disease Education and Resource Center (ADEAR), and Google. ADEAR is a cumulative database maintained by the National Institutes of Health as part of the Combined Health Information Database. Search terms included rivastigmine, Fkebn, EAJA713, and EAJA-713. The bibliographies of retrieved articles also were searched for relevant articles. RIVASTIGMINE

Rivastigmine tartrate* is a carhamate derivative that reversibly inhibits the metabolism of acetylcholinesterase (AChE) and hutyrylcholinesterase (BuChE), preferentially in the central nervous system (CNS). Rivastigmine’s chemical name is ‘Trademark:

1638

Exelon@ (Novartis Pharmaceuticals

Corporation,

East Hanover, New Jersey).

B.R. Williams et al.

(S)-N-ethyl-N-methyl-3-[ l-l(dimethylamino)ethyl]-phenyl carbamate hydrogen(2R,3R)-tartrate (Figure 3), and it has a molecular weight of 400.43 g. Rivastigmine is a white to off-white, fine crystalline powder that is soluble in water and alcohol.ls Rivastigmine is supplied in 1.5, 3.0-, 4.5, and 6.0-mg capsules for oral administration. l8 Rivastigmine also is available in an oral solution with a dosing syringe that is calibrated for the same 4 doses, all with a concentration of 2 mg/mL. Both formulations have the same dosing and titration schedule. l8 Mechanism

ofAction

Rivastigmine’s precise mechanism of action is unknown. It hinds to both the esteratic and ionic sites of AChE, preventing the enzyme from metabolizing ACh.19 Several isoforms of AChE have been identified, with identical amino acid sequences, hut with different posttranslational modifications, anatomic and microanatomic locations, and functions. 2o The predominant form of AChE in the 0

CH3 CH2

AI

NTH, F>

Rivastigmine tartrate

. C4H606 CH3 I

N

\ CH3

Hydrolysis

+

H20

1

FI F,

OH

P3

N

\/CH3

+

Rivastigmine hydrolyzed to decarbamylated metabolite

Figure 3. Chemical

structure

of rivastigmine

tartrate.

1639

CLINICALTHERAPEUTICS@

cortical and hippocampal regions of the normal brain is the membrane-hound globular tetrameric form, G4, with a small amount of the monomeric form, Gl. Due to a selective loss of the G4 form in patients with dementia, the Gl form predominates. In patients with AD, rivastigmine preferentially inhibits the Gl form of AChE compared with the G4 form.21 Rivastigmine also inhibits the activity of BuChE, which is more active in patients with AD.22,23 Rivastigmine selectively inhibits cholinesterases in the CNS, using cerehrospinal fluid (CSF) activity as a marker.22 The inhibition of AChE and BuChE has been demonstrated for up to 12 months in patients with mild dementia.23 Although AChE selectively hydrolyzes ACh, BuChE also degrades other substrates such as various neuroactive peptides. Therefore, inhibiting both AChE and BuChE results in higher levels of ACh inhibition in the hrain.22 Over the course of AD, AChE activity decreases progressively, whereas BuChE activity increases progressively 23 Therefore, in early stages of AD, inhibition of AChE is more important, hut as the disease progresses, BuChE inhibition contributes more to reducing the cholinergic deficit. Both AChE and BuChE are associated with formation of amyloid plaque and NFTs, the 2 pathologic criteria for the diagnosis of AD. Advanced plaque formation shows as much as 87% BuChE activity and 80% AChE activity, which has been demonstrated to accelerate the formation of heta-amyloid.23 PharmacokineticslPharmacodynamics

Absorption and Bioovailability

The pharmacokinetic and pharmacodynamic characteristics of rivastigmine are Rivastigmine is administered orally and is reported presented in Table I. 18,19,22,25 to he absorbed rapidly and completely in healthy adults, reaching peak plasma concentration in -1 hour, with absolute hioavailability of -36% (3-mg dose).19 This suggests a significant first-pass effect. According to the manufacturer, rivastigmine shows linear pharmacokinetics up to 3 mg, hut at higher doses those properties become nonlinear, whereby doubling the dose from 3 to 6 mg BID results in a 3-fold increase in the area under the plasma concentration-time curve (AUC).l’ However, a study by Cutler et al,” conducted in 18 patients with AD, noted a linear relationship between dose and AUC at dosages of 1 to 6 mg BID. Administering rivastigmine with food delays absorption by delaying time to reach maximum concentration (T,,,) by 90 minutes (Tmax is about 0.5-2.0 hours); it also lowers maximum concentration (Cmax>by 30% and increases AUC by 30%.19 Taking rivastigmine with food enhances its hioavailability and increases tolerability; gastrointestinal (GI) AEs may he associated with high peak plasma levels. The pharmacokinetic half-life of rivastigmine in patients with AD is -1.5 hours, whereas the pharmacodynamic half-life is -10.0 hours.22 This is because rivastigmine hinds to the esteratic site of the AChE enzyme, hut dissociates much 1640

B.R. Williams et al.

Table I. Pharmacokinetic

and pharmacodynamic

characteristics

of rivastigmine.*

Characteristic

‘8,‘9,22,25

Value

Bioavailability

36%

T

052.0

Absorption

Rapid and complete

Peak plasma concentration

Ih

’max

h

Effect with food T

’max C max

t90

min

AUC

?30%

J30%

Half-life Pharmacokinetic

I.5 h

Pharmacodynamic

10.0 h

Protein binding

40%

Volume of distribution

I .8&2.7 L/kg

Metabolism Site (cytochrome

P450 isozymes)

Drug interactions

Nonhepatic No

Dosage Starting

I .5 mg BID

Maximum

6 mg BID (I 2 mg/d)

Titration Adjustment

required

Vest

for impairment

Hepatic Renal Elimination

No No Renal

Special populations Pregnant

Category

Lactating

Unknown

Pediatric

Unknown

Geriatric

Oral clearance J30%

T max = time to maximum concentration; concentration-time *Trademark tI.5.mg

C,,,ax = maximum concentration; AUC

B rating

= area under the plasma

curve.

Exelon@ (Novartis Pharmaceuticals Corporation, East Hanover, New Jersey).

increments after tolerability has been demonstrated at the previous dosage for 22 weeks

more slowly than ACh. This “pseudo-irreversible” action explains why the ChE inhibition of rivastigmine in the brain lasts much longer (mean, 10 hours) than the short plasma half-life of the drug would predict. 19,22The biologic half-life of rivastigmine is reported to he I1 hour in younger adults.” 1641

CLINICALTHERAPEUTICS@

Distribution

and Elimination

Rivastigmine is reported to he widely distributed with a volume of distribution of 1.8 to 2.7 L/kg in healthy adults; it penetrates the blood-brain harrier and is -40% hound to plasma proteins. l9 The primary metabolite of rivastigmine, NAP 226-90 (ZNS 114-666), appears to he inactive. It exhibits a volume of distribution of 4.3 to 5.9 L/kg and is distributed to the CNS.19,22 Renal excretion of the sulfate conjugate of NAP 226-90 is the primary route of elimination, with no parent drug detected in the urine; ~1% of the administered dose is excreted in the feces. Essentially all of rivastigmine’s metaholites appear to he eliminated within 24 hours. l9 Metabolism

Rivastigmine undergoes extensive metabolism by ChE-mediated hydrolysis to the decarbamylated metabolite, NAP 226-90, without involvement of the major cytochrome P450 (CYP450) isozymes (Figure 3). The metaholite may undergo N-demethylation as well as conjugation. Compared with healthy adults, no apparent difference in the ability of patients with AD to metabolize rivastigmine has been noted. l9 Special Populations

Hepotic Disease

According to the manufacturer’s literature,” mean clearance of rivastigmine following a single, 3-mg dose was 60% lower in 10 patients with mild (Child-Pugh26 score 5-6) or moderate (Child-Pugh score 7-9) hepatic impairment than in 10 healthy subjects.ls The pharmacokinetic properties of rivastigmine were investigated in 10 patients with hepatic cirrhosis. 25 Compared with healthy adults, the AUC was increased 2.3-fold for the parent drug (P < 0.01) and reduced by 20% (P = 0.04) for the metabolic products. The investigators concluded that no dosing adjustment is needed in clinical practice, because the starting dosage remains the same as for patients without hepatic impairment and dosages are increased to maximum tolerance or to 6 mg BID.25 Renal Disease

The same study also assessed the disposition of rivastigmine in adults with creatinine clearance rates (CCRs) of ~10 mUmin. Compared with healthy adults, the AUC of the parent drug was increased by 40% (P = 0.03) and the AUC of its metaholite was increased by 50% (P = 0.02).25 According to the manufacturer’s literature,ls the mean renal clearance of rivastigmine following a single, 3-mg dose is 64% lower in patients with moderate renal impairment (glomerular filtration rate [GFR] lo-50 mUmin) than in healthy subjects (GFR >60 mUmin). 1642

B.R. Williams

et al.

However, for unexplained reasons, the mean oral renal clearance in patients with severe renal impairment (GFR ~10 mUmin) was 43% higher than that in healthy people. l8 As in patients with hepatic impairment, dose adjustment does not appear to he warranted because the starting dose is low and followed by titration to tolerance or the maximum dose.25

The manufacturer reports that the mean renal clearance of rivastigmine after a single, 2.5mg oral dose was 30% lower in 24 patients >60 years of age than in younger patients. l8 An increase of 10% to 26% in the elimination half-life of rivastigmine also has been reported. l9 Treatment is initiated at a low dose and titrated upward to patient tolerance. No alterations in initial dosing are recommended to compensate for altered CCR or half-life.ls Rivastigmine is not indicated for use in any disorder that is known to occur in children or adolescents. Sex and Race

No studies have been conducted specifically to investigate the effect of sex or race on the pharmacokinetic properties of rivastigmine. l8 Pregnancy

Rivastigmine has a pregnancy category B rating, revealing no evidence of teratogenicity in reproduction studies conducted in pregnant rats.ls No wellcontrolled studies have been conducted in pregnant women, and because animal studies are not always predictive of human response, the use of rivastigmine should he limited only to patients in whom the potential benefit justifies the potential risk to the fetus. Similarly, no well-controlled studies have been conducted in pediatric patients or nursing mothers, nor is evidence available on whether rivastigmine is excreted in human breast milk; therefore, rivastigmine is not indicated for nursing mothers. l8 The authors’ literature search did not reveal any case reports or other evidence regarding the clinical use or toxicity of rivastigmine during pregnancy Clinical Trials

The efficacy and tolerability of rivastigmine have been investigated in several randomized, double-blind, placebo-controlled trials conducted in patients with AD. Eligibility criteria for potential subjects included meeting the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) for probable AD27 and a Mini-Mental State Examination (MMSE)28 score of 10 to 26. Standard tests for efficacy in clinical trials include the Alzheimer’s Disease Assessment-Scale cognitive suhscale (ADAS-cog)29 to measure cognition, 1643

CLINICALTHERAPEUTICS@

the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-P~US)~~ to measure change in function over time (this test evaluates 3 major areas-cognition, behavior, and activities of daily living [ADLs]), and the Progressive Deterioration Scale (PDS)31 to assess subjects’ ability to perform ADLs. An early tolerability study was conducted in 50 patients with AD with a mean age of 68 years (range, 45-90 years) to assess a daily dose of rivastigmine (ENA713) up to 12 mg/d.32 Patients were randomized to receive placebo (n = 10) or ENA(n = 40), up to 12 mg/d, during a 9-week, forced-titration schedule. Those assigned to receive active drug took the medication either BID (n = 20) or TID (n = 20). Dosing was started at 2 mg/d for study days 1 to 3 and then increased to 12 mg/d during weeks 8 and 9. Measures to assess tolerability included physical examination, electrocardiogram (ECG), clinical laboratory evaluations, and reported AEs. The most common AEs experienced by patients receiving ENAare listed in Table II.22,32-33Nausea was the only AE that occurred more commonly in the treatment group than in the placebo group, and that was among patients assigned

Table II. Adverse

effects commonly

percentages

of patients

encountered

receiving

during

rivastigmine

trials (expressed

as

rivastigmine). Study

Adverse

Sramek et al,

Cutler et al,

I99632

199822

I99833

I99934

(N = 50)

(N = 18)

(N = 699)

(N = 725)

48/2O”t

50”

271 I6”t

34”

20lNR

I 4*i

Effects

Corey-Bloom

et al,

Rosler et al,

Gastrointestinal Nausea

48

50

Diarrhea

38

44

Vomiting

28

39

Anorexia Abdominal

17”

12”

pain

Central nervous system Headache

65

61

Dizziness

40

44

28

Fatigue

19” 241 I4”t

20”

I O/NR”t

23”

3/NR”t

IO

44 Malaise NR =

Not

reported.

*Reported

in high-dose

tReported

during

1644

group.

titration/maintenance

phase

B.R. Williams

et al.

to the TID regimen (P < 0.05). Three patients assigned to ENAwithdrew, all because of AEs; 2 patients in the placebo group withdrew for other reasons (1 did not return, 1 misdosed and elected to discontinue). The authors found no clinically significant changes in vital signs, ECGs, or laboratory values during the study The investigators concluded that doses of ENAup to 12 mg/d were well tolerated, without severe AEs.~~ In a 26-week study in the United States, investigators from 22 research centers assessed 699 patients with mild to moderately severe probable AD.33 Eligibility criteria included DSM-IV’ AD diagnostic criteria in addition to the NINCDSADRDA and MMSE criteria. Patients were randomly assigned to receive either rivastigmine 1 to 4 mg/d (low dose) or 6 to 12 mg/d (high dose) or placebo; each was given in 2 divided doses during a 7-week fixed-dose titration period, followed by a flexible-dose period during weeks 8 to 26. Efficacy was measured using the ADAS-cog,* CIBIC-Plus,+ and PDS.* The mean improvements in the ADAS-cog score at 26 weeks of treatment for the rivastigminetreated patients compared with those receiving placebo were 1.9 units in the l- to 4-mg treatment group (P < 0.05) and 4.9 units in the 6- to 12-mg treatment group (P < 0.001). Throughout the study, according to CIBIC-Plus scores, patients in the high-dose group demonstrated no deterioration or less than that demonstrated by patients in the placebo group (P < 0.01). At week 26, less deterioration was found in the low-dose group than in the placebo group (P < 0.05). By the end of the study, only high-dose rivastigmine showed a difference from placebo in the PDS scores (P < 0.001).33 AEs that were commonly encountered during the study are shown in Table II. AEs typically involved the GI system, and were more common during the titration phase and among those in the high-dose group. The dropout rates were 35%, 15%, and 16%, for the high-dose, low-dose, and placebo groups, respectively AEs were the most frequently cited reason for withdrawal in all groups.33 In a second 26-week, double-blind, placebo-controlled, parallel-group study3+ conducted in 45 centers in Europe and North America, 725 patients were randomly assigned to receive either 1 to 4 mg/d or 6 to 12 mg/d rivastigmine or placebo, given in 2 divided doses during 12-week forced-titration and 14-week maintenance phases. Subjects were aged 50 to 85 years, met NINCDS-ADRDA and DSM-IV’ diagnostic criteria for probable AD, and had MMSE scores of 10 to 26. Efficacy was assessed using the ADAS-cog, CIBIC-Plus, and PDS scales. The mean improvements in the ADAS-cog score in the rivastigmine-treated patients compared with placebo were 0.2 kSeventy-point scale, with higher scores indicating the worse disease. Scores typically are compared with baseline. A negative score indicates improvement. rScale: 1 to 7 (1 = improved compared with baseline, $ = unchanged from baseline, 7 = worse compared with baseline). %ne hundred-point scale, with higher scores indicating improvement compared with baseline.

1645

CLINICALTHERAPEUTIC?

unit in the l- to 4-mg treatment group (P = NS) and 2.6 units in the 6- to 12-mg treatment group (P < 0.05). The difference between the 6- to 12-mg/d regimen and the l- to 4-mg/d regimen was statistically significant (P < 0.05). The difference hetween the 6- to 12-mg regimen and placebo also was significant (P < 0.001). No statistically significant difference was found between the l- to 4-mg/d regimen and placebo. At week 26, the CIBIC-Plus score showed significant improvement in patients receiving high-dose rivastigmine compared with those receiving placebo (P < 0.05). No significant difference was found between the low-dose and placebo groups. PDS scores showed significant improvement in patients in the high-dose group compared with those in the placebo group at week 26 (P < O.OS>,hut only when the last observation was carried forward, not in subjects completing the tria1.33 AEs were more common among members of the high-dose group and primarily affected the GI system (Table II). AEs occurred in 91% of the high-dose group compared with 71% and 72% of the low-dose and placebo groups, respectively (P < 0.05). Similarly, dropout rates were significantly higher in the high-dose group (32.6%) than in the low-dose (14.0%) or placebo (13.0%) groups. Body weight decreased by a mean of 1.39 kg in the high-dose group and 0.13 kg in the low-dose group, hut increased by a mean of 0.72 kg in the placebo group by the end of the study3+ Two open-label trials 35,36have extended the findings of clinical trials by investigating the use of rivastigmine treatment for an additional 26 weeks. Both studies were conducted in patients who had participated in a 26-week study reported by Corey-Bloom et al. 33 The first study35 included 532 subjects who either completed the double-blind study (n = 513) or withdrew during that trial. The patients who entered the extension study received rivastigmine 1 mg BID for the first week. The dosage was increased, according to patient tolerance of AEs, in increments of 1 mg BID every week, up to a maximum dosage of 6 mg BID. The ADAS-cog was used to assess efficacy and included measurements from the double-blind trial through the completion of the 26-week extension, for a total of 52 weeks of ohservation.35 Of the 532 subjects who participated in the extension trial, 125 were from the high-dose (6-12 mg/d) group, 15 1 were from the low-dose (l-4 mg/d) group, and 144 had received placebo. At the end of the 52-week extension, 10% of suhjects receiving the high dose showed an improvement of 27 points from baseline (week 0) on the ADAS-cog compared with 4% and 3% of the low-dose and placebo groups, respectively The difference was significant between the high-dose and placebo groups (P = 0.021). The results suggest that clinical benefit from rivastigmine continues, at least in some patients, for 21 year.35 The other open-label tria136 assessed retrospectively the relationship between disease severity and response to rivastigmine. Subjects included 187 of 235 patients who were enrolled in the placebo arm of a 26-week clinical tria1.33 In this 26-week extension study, patients received rivastigmine, 1 mg BID, with dose titration at a rate of 1 mg BID per week to a maximum of 6 mg BID.36 Cognition 1646

B.R. Williams

et al.

was assessed using the ADAS-cog at weeks 26 (start of open-label treatment), 38, 44, and 52 of treatment. Patients were classified with respect to disease progression based on the change in cognition scores seen during the 26-week clinical tria1.33 Slow progression was defined as <4-point deterioration on the ADAS-cog, and rapid progression was defined as 24-point deterioration.36 At week 26 (start of open-label treatment) the slowly progressive patients had significantly lower scores than the rapidly progressive patients (17.5 vs 33.5, respectively; P < 0.001). During the trial, however, the rapidly progressive patients exhibited a marked improvement (mean change, 4.97 points) compared with the slowly progressive patients (1.03 points; P < 0.05). At subsequent time points, the cognitive scores for the rapidly progressive patients decreased, hut were still significantly better than those of the slowly progressive patients (P < 0.05).36 Similar results were noted for overall function, as measured by the PDS; the slowly progressive patients demonstrated significantly improved function at the start of the open-label study (week 26) compared with the rapidly progressive patients (P < 0.001). However, the reverse was true at weeks 38 and 44 (P < 0.05). At week 52, no statistically significant between-group differences were found.36 To assess tolerability, the same patients were checked for AEs and discontinuation rate. Almost all patients experienced 21 AE (96.5% of patients receiving 6-12 mg/d rivastigmine, 94% of those receiving <6 mg/d). GI complaints were the most common AEs for both rapidly and slowly progressive patients.36 Approximately 26.5% of slowly progressive patients and 24.0% of rapidly progressive patients discontinued treatment, with the most common reason being AEs. Adverse

Events

The AEs most often encountered during clinical trials are shown in Table II. Most of the AEs involved the GI system and were typically mild to moderate.22,32-33 Other AEs noted during trials included agitation, asthenia, coughing, myalgia, rhinitis, somnolence, sweating, and urinary incontinence.32,33 No significant changes in vital signs, ECGs, or clinical laboratory values, including hepatic function tests, were reported in any of the trials. One case of spontaneous esophageal rupture was reported during rivastigmine therapy3’ The rupture occurred after an episode of severe vomiting after the patient took a dose of 4.5 mg rather than the prescribed 1.5 mg. It is quite possible, therefore, that the rupture was precipitated by the vomiting rather than by the medication.38 Drug Interactions

Because rivastigmine is primarily metabolized through hydrolysis by esterases, and only minimally metabolized through the CYP450 isozymes,19 no pharmacokinetic interactions with drugs metabolized through the CYP450 isozymes are ex1647

CLINICALTHERAPEUTICS@

petted. The literature search did not reveal any studies or case reports concerning such interactions. Drugs that can produce additive pharmacodynamic effects (eg, cholinesterase inhibitors and parasympathomimetics) should not he administered concomitantly with rivastigmine. Coadministration of rivastigmine with these drugs could increase the effect of rivastigmine and increase the potential for toxicity l8 In contrast, anticholinergic drugs may decrease the effects of rivastigmine because the latter increase the cholinergic effect. Pooled data from clinical trials (N = 2459) indicated that antispasmodics, anticholinergics, and propulsive agents were more likely to cause AEs and require treatment in patients receiving rivastigmine than in those receiving placebo (P = 0.037).39 The combination of rivastigmine and diuretics was associated with severe AEs (P = 0.017) and body weight loss (P = 0.010).39 Salicylate and rivastigmine combinations were associated with body weight loss (P = 0.040) and malaise (P = 0.007). The authors concluded that, despite the statistical significance, the interactions, including the previously mentioned severe AEs, were not clinically relevant.39 Dosage

and Administration

The suggested starting dosage of rivastigmine for the management of mild to moderate dementia is 1.5 mg BID, which, if well tolerated after a minimum of 2 weeks of treatment, may he increased to 3.0 mg B1D.l’ Subsequent increases to 4.5 mg and 6.0 mg BID may he attempted after 22 weeks at the previous dose. The maximum dosage is 6 mg BID (12 mg/d). l8 Evidence from the clinical trials shows that doses at the higher end (9-12 mg/d) may he more heneficia1.33,33 If AEs suggest intolerance (eg, severe nausea, vomiting) during treatment, the patient should he instructed to skip several doses and then restart treatment at the same or next lower dose.ls If treatment is disrupted for more than several days, it should he reinitiated with the starting dosage (1.5 mg BID) and titrated hack to the maximum tolerable dosage. Because food increases drug tolerability, rivastigmine should he taken with food in 2 divided doses, morning and evening.ls Contraindications

Rivastigmine is a carbamate derivative and is therefore contraindicated in patients with carhamate hypersensitivity Risk versus benefit should he considered when the following medical problems exist: asthma (because hronchoconstriction may he precipitated); cardiovascular conditions, such as hradycardia and sick sinus syndrome (because a vagotonic effect on the heart may exacerbate preexisting conditions); epilepsy (because seizures may occur); GI or urinary tract obstruction (because increased activity of the GI tract or urinary bladder may he harmful); and current or previous peptic ulcers (because rivastigmine increases gastric acid secretion, which may exacerbate or reactivate the condition).ls 1648

B.R. Williams

et al.

Pharmacoeconomics

The literature search revealed 3 articles that discussed cost implications associated with rivastigmine treatment. All 3 articles were based on a hazard model of disease progression that used the MMSE to measure cognitive decline.+O The model was derived using data from two 26-week clinical trials of rivastigmine.33,33 Hauher et a131 estimated the cost-savings potential of rivastigmine treatment over 2 years, with monetary values expressed in 1997 Canadian dollars. The primary outcome measure was delay in progression to the next stage of AD; stages were defined as mild (MMSE score of 21-26), mild to moderate (score of 1%20), moderate (score of lo-14), or severe (score of O-9). The researchers estimated an overall delay to subsequent AD stages to he 5 days at 6 months, 36 days at 1 year, and 137 days after 2 years of treatment. Cost savings per day per patient at the same time periods were Can $0.71, Can $2.51, and Can $4.93. The authors concluded that the primary cost savings for patients with mild dementia were realized from the delay in transition to moderate AD. For those who began treatment in the moderate stage, cost savings were primarily attributable to the delay in institutionalization during the first year of treatment. A similar studyq2 using the 2 pivotal clinical trials33,33 estimated the cost savings associated with rivastigmine treatment for US patients with mild to moderate AD. The primary outcome measure was cost savings relative to a delay in institutionalization. Stages of AD were defined as mild (MMSE score of 21-30), moderate (score of 11-20) or severe (score of O-10). As was found in the Canadian study,+l rivastigmine delayed progression of AD to later stages. Patients with mild dementia remained in the mild stage for an additional mean of 56 days over 2 years and, after progressing to moderate AD, spent an additional mean of 69 days in that stage. Patients who began rivastigmine treatment while in the moderate stage remained in that stage for an additional mean of 51 days.32 Cost savings, exclusive of drug costs, were realized during the first 6 months of treatment and persisted through 2 years. Savings at 6 months ranged from US $132 for patients with mild AD to US $137 for those with moderate AD. At 2 years, the savings were US $4389 and US $2290, respectively The savings were attributed primarily to the delay in institutionalization.32 Baladi et alq3 assessed the clinical meaning and cost implications of treatment from the results of 2 clinical trials of rivastigmine.33,33 A convenience panel of 9 Canadian physicians provided opinions regarding the clinical relevance of statistically significant findings on the ADAS-cog, CIBIC-Plus, PDS, MMSE, and Global Deterioration Scale (GDS).35 The panel reviewed results from study participants who received a high dose of rivastigmine (6-12 mg/d) during the trials. Five of the 9 panelists responded and offered opinions; the entire panel reviewed the responses. Four of the 5 panelists (56%) considered the results of the ADAS-cog, CIBIC-Plus, and PDS, hut not the MMSE, to he clinically relevant. Three panelists 1649

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considered the GDS scores to he clinically relevant. According to the panel, the clinical importance of the findings was based on the positive effects on patients and caregivers that might reduce the use of health care resources and delay the need for in-home care or institutionalization.33 The authors estimated that rivastigmine treatment would produce net direct health care costs per patient of Can $760 at 1 year and savings of Can $297 at 2 years. During the first year, medication cost was estimated to exceed other medical care costs, whereas the reverse was true for the second year. Indirect costs, which included caregiver time missed from work or other activities, would he reduced by Can $437 per patient at 1 year and by Can $1626 at 2 years. This small group of Canadian clinicians concluded that cost savings would he realized after 2 years of treatment. The primary factors associated with cost savings were stabilized patient health and delayed institutionalization.33 SUMMARY

AND

CONCLUSIONS

Rivastigmine is a carhamate derivative that reversibly inhibits the metabolism of AChE and BuChE, preferentially in the CNS. It has a short biologic half-life with an extended pharmacologic half-life due to slow dissociation from the enzyme. Clinical trials have demonstrated improvement or maintenance of cognitive function, behavioral function, and ability for self-care among patients with mild to moderate AD. At dosages of 6 to 12 mg/d, patients may remain at or above their baseline function for as long as 6 months, followed by a slow decline. Openlabel trials have demonstrated clinical effects for up to 52 weeks. Patients started on rivastigmine therapy at earlier stages of AD appear to fare better than those in whom therapy is begun at later stages. Therapy is instituted at a dosage of 1.5 mg BID and may he increased at increments of 1.5 mg BID at intervals of 22 weeks, up to a maximum of 6 mg BID. A slower titration schedule of every 4 weeks may reduce AEs and improve tolerability Because rivastigmine is titrated to clinical effect, no dose adjustment appears necessary for elderly patients or for those with compromised hepatic or renal function. AEs are generally mild to moderate and primarily affect the GI tract. Nausea, vomiting, and anorexia may he reduced by giving the medication with food, which slows the rate of absorption without compromising hioavailahility To date, clinically significant drug interactions have not been reported with rivastigmine. The potential exists, however, for additive effects with other parasympathomimetic drugs, or for antagonistic effects with anticholinergic agents. Treatment with rivastigmine may lead to a reduced cost of health care for patients with AD who take the medication for up to 2 years. Cost savings are minimal during the first year of treatment, particularly for those with mild disease, hut increase during the second year. Cost savings occur earlier for those with moderate AD. Most savings are realized from a delay in institutionalization. 1650

B.R. Williams et al.

Rivastigmine is an effective It is generally well tolerated, Although it does not appear patients to maintain function

treatment for the symptoms of mild to moderate AD. provided that the dosage is not increased too rapidly. to halt or reverse the progression of AD, it may allow and remain at home for a longer period of time.

ACKNOWLEDGMENT

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Address correspondence to: Mark A. Gill, PharmD, Professor of Clinical Pharmacy, University of Southern California School of Pharmacy, 1985 Zonal Avenue, #208A, Los Angeles, CA 90089. E-mail: [email protected] 1653