Rivastigmine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.31.2021
Released 05.17.2000
Expires For CME 03.31.2024

Rivastigmine

Author: K K Jain MD†

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Rivastigmine

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Introduction

Historical note and terminology

One of the earliest approaches for Alzheimer disease treatment was augmentation of cholinergic activity, which was based on a loss of acetylcholine in the frontal cortex and the hippocampus. Physostigmine, 1 of the earliest cholinesterase inhibitors to be studied, produced modest improvement in cognition in some patients by inhibiting intrasynaptic degradation of acetylcholine (06). Its use was limited because of the frequent dosing required and the severe adverse reactions it caused. In 1993, tacrine was the first cholinesterase inhibitor to be approved for use in Alzheimer disease, but it was discontinued because of its hepatotoxicity. In 1996, donepezil, a selective cholinesterase inhibitor, was approved for use in Alzheimer disease. In 2000, rivastigmine, a pseudoreversible cholinesterase inhibitor, was approved by the Food and Drug Administration, having been previously approved and used in several other countries. A transdermal preparation of rivastigmine was approved by the FDA in 2007.

Pharmacology

Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:

• Reversible inhibitors: donepezil, galantamine.
• Pseudoreversible inhibitors (carbamate derivatives): physostigmine, rivastigmine.
• Irreversible inhibitors: metrifonate.

Pharmacodynamics. Rivastigmine is an acetylcholinesterase inhibitor that facilitates cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons.

Rivastigmine (chemical structure)

(Contributed by Dr. K K Jain.)

Thus, rivastigmine may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer disease. Rivastigmine is a carbamate derivative that binds to the steric site of the acetylcholinesterase and dissociates slowly; thus, it provides a longer duration of action than tacrine and donepezil, which are short-acting agents, because binding to acetylcholinesterase is hydrolyzed within minutes. In addition to acetylcholinesterase, rivastigmine inhibits butylcholinesterase, and because of this dual inhibition, it can optimize cholinergic function. Rivastigmine markedly inhibits cerebrospinal fluid acetylcholinesterase after a single oral dose of 3 mg; it also has central nervous system selectivity over the peripheral inhibition of acetylcholinesterase.

An oral 3 mg dose decreases acetylcholinesterase activity in cerebrospinal fluid by approximately 40% within the first 1.5 hours after administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with Alzheimer disease, inhibition of acetylcholinesterase in cerebrospinal fluid by rivastigmine was found to be dose-dependent up to 6 mg given twice a day (the highest dose tested). In addition to anticholinesterase activity, rivastigmine directs amyloid precursor protein processing away from beta secretase1 towards nonamyloidogenic α-secretases, which can be therapeutically exploited for disease-modifying effect that goes beyond symptomatic treatment for Alzheimer disease (25).

Alterations in the clinical and cognitive status of patients receiving rivastigmine are paralleled by changes in regional cerebral blood flow as measured by SPECT. These values are enhanced in responders and reduced in nonresponders.

Pharmacokinetics. Important points pertaining to pharmacokinetics include the following:

	• Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a result of the drug’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose.
	• Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brain barrier.
	• Rivastigmine is rapidly and extensively metabolized (half-life in plasma approximately 1 hour) primarily through cholinesterase-mediated hydrolysis to the decarbamoylated metabolite. Total plasma clearance of rivastigmine was approximately 130 L/h after a 0.2 mg intravenous dose, and it decreased to 70 L/h after a 2.7 mg intravenous dose.
	• Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14-C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. No accumulation of rivastigmine or the decarbamoylated metabolite is present in patients with Alzheimer disease.
	• Transdermal rivastigmine maintains steady drug levels in the bloodstream as compared to fluctuations with the capsule form of the drug. A study to measure exposure to rivastigmine from a transdermal patch has shown that Cmax of rivastigmine and its metabolite NAP226-90 is highly correlated with the corresponding under the curve (AUC) 24h values, confirming the role of a time point closer to Cmax for an effective AUC measurement of area of rivastigmine or the metabolite (29). Transdermal rivastigmine enables maintenance of a lower peak of drug concentration, fewer gastrointestinal side effects, and an efficacy like the oral capsules of rivastigmine. Despite the advantages of transdermal rivastigmine, the effects of environmental factors such as fever or skin abrasions or tears on drug pharmacokinetics are unknown, and the need for titration to the target dose is not eliminated. A prospective, 24-week, observational, post-marketing surveillance study found that the rivastigmine transdermal patch is safe and tolerable for Alzheimer patients (24).
	• Estrogen receptor α (ESR1) gene contributes to interindividual variability in response to treatment with cholinesterase inhibitors (26). This correlates with the observation that women are more sensitive to therapy and experience less cognitive decline.

Clinical trials

The safety and efficacy of rivastigmine was evaluated in phase 3 multicenter, randomized, double-blind, and placebo-controlled parallel-group trials. Primary efficacy parameters included evaluation of cognition with the cognitive subscale of the Alzheimer Disease Assessment Scale. Overall clinical effect was assessed using the clinician's Interview Based Impression of Changes Plus, which incorporates caregiver data. The impact of rivastigmine on improving daily activities was also assessed using the Progressive Deterioration Scale. Results in patients with mild to moderately severe and probable Alzheimer disease showed that rivastigmine improved cognition, participation in daily activities, and global evaluation ratings.

The approval of rivastigmine was based on studies involving more than 3900 patients, the largest phase 3 program for an Alzheimer disease medication.

A retrospective analysis of pooled data from 3 randomized, placebo-controlled, double-blind, 6-month trials involving 2126 patients with Alzheimer disease suggests that rivastigmine 6 to 12 mg/day may benefit subjects with more severe disease as well as subjects with mild to moderate impairment (04).

Results of a 6-month, double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer disease shows that the patch provides efficacy equal to the highest doses of capsules with a superior tolerability profile and may offer convenience important to many caregivers and patients (30).

A 26-week, randomized, double-blind, placebo-controlled trial showed that rivastigmine administered as a BID or TID regimen significantly benefited cognitive, functional, and global performances in Alzheimer disease patients (10). The TID regimen was better tolerated and enabled titration to higher doses, leading to improvement of dose-related efficacy of rivastigmine.

In a multicenter, open-label, randomized trial, slow escalation of the dose of rivastigmine did not show greater effectiveness or tolerability in comparison to an escalation applied in accordance with usual clinical practice (01).

A 24-week, randomized, double-blind, placebo-controlled, multicenter trial to test the efficacy and tolerability of the rivastigmine transdermal patch in patients with mild to moderate Alzheimer disease showed a favorable skin tolerability profile and confirmed that the benefits of therapy were not confounded by significant skin irritation problem (05). The ACTION (ACTivities of daily living and cognitION) trial is designed to evaluate the efficacy and safety of low-dose versus high-dose rivastigmine transdermal patch measuring 15 cm (currently approved size 10 cm) in patients with severe Alzheimer disease (07). This 24-week prospective, randomized, parallel-group, double-blind trial uses a design that does not include a placebo group.

A retrospective analysis of a large randomized, placebo-controlled trial of Alzheimer disease patients treated with transdermal rivastigmine or rivastigmine capsule compared to placebo showed greatest treatment effects in patients with more advanced dementia who received rivastigmine, and these were most likely due to greater decline in the patients treated with placebo (08).

A systematic review of controlled clinical trials showed that rivastigmine (6 to 12 mg daily orally or 9.5 mg daily transdermally) showed better outcomes for rate of decline of cognitive function as well as activities of daily living in patients with mild to moderate Alzheimer disease in comparison with placebo (02).

In a multicenter, prospective, open-label study on patients with mild to moderate Alzheimer disease, efficacy and tolerability of rivastigmine patch therapy were not associated with severity of white matter hyperintensities in patients with Alzheimer disease; some improvement in frontal function was observed in those with minimal white matter lesions (23).

Indications

Indications include the symptomatic treatment of mild to moderately severe Alzheimer dementia and mild to moderate dementia related to Parkinson disease. Ongoing studies are examining the effect of rivastigmine in patients with severe Alzheimer disease.

Off-label uses

There was some evidence of benefit of rivastigmine in vascular cognitive impairment in a clinical trial, but a significant proportion of patients discontinued treatment because of side effects (03).

Rivastigmine has been used for improving memory in schizophrenia.

Rivastigmine lowers intraocular pressure significantly and may be of potential use in glaucoma therapy.

Rivastigmine has been used by patients with traumatic brain injury with moderate to severe memory deficits.

Preliminary findings of another placebo-controlled, randomized clinical trial suggest that rivastigmine may improve cognitive processing speed by enhancing compensatory brain activation in patients with multiple sclerosis (14).

A randomized, double-blind, placebo-controlled, crossover study showed that rivastigmine with HIV-associated neurocognitive disorders (HAND) seemed to improve psychomotor speed (27).

Rivastigmine is an effective add-on to treatment of patients with chronic posttraumatic stress disorder (09).

A randomized, double-blind, placebo-controlled, crossover, single-site study of the rivastigmine transdermal patch in patients Parkinson's disease who had mild cognitive impairment showed significant improvement on a performance-based measure of cognitive abilities (18).

Results of a small randomized trial indicate that transdermal rivastigmine does not provide significant cognitive benefits in patients with HIV-associated cognitive impairment on stable antiretroviral therapy (20).

A randomized trial of rivastigmine for postural instability in Parkinson disease with dementia has shown that it may improve postural control (19).

Rivastigmine can improve gait stability to help reduce the risk of falls in patients with Parkinson disease (13).

Goals and duration of treatment

If the initial dose is well-tolerated after a minimum of 2 weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to a maximum of 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of 2 weeks of treatment at that dose level. Maintenance treatment can be continued for as long as necessary. The clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. Discontinuation should be considered when evidence of a therapeutic effect is no longer present. Although individual response to rivastigmine is difficult to predict, generally available neuropsychological and quantitative EEG data may be useful for predicting response to rivastigmine in patients with Alzheimer disease.

The rate of disease progression for patients with mild to moderate Alzheimer disease appears to predict response to rivastigmine treatment. Patients with more rapidly progressive disease are more likely to benefit from rivastigmine therapy. An increase in plasma amyloid-beta(1-42) level after initiation of treatment might be a novel biochemical predictor of long-term rivastigmine treatment efficacy in Alzheimer disease (28).

In an open-label, prospective study, rivastigmine transdermal patch was effective in maintaining cognitive function over 18 months of treatment in patients with mild to moderate Alzheimer disease (12). In patients with mild to moderate Alzheimer disease who have previously experienced functional and cognitive decline while receiving the 10 cm(2) patch, increasing the transdermal rivastigmine dose to the 15 cm(2) patch has a favorable benefit-risk profile (11). It is a valid option as it slows functional deterioration without compromising tolerability. Findings of a retrospective study indicate that 13.3 mg per 24-hour rivastigmine patch has a broader cognitive efficacy than a 4.6 mg per 24-hour patch across a range of Severe Impairment Battery (SIB) items in patients with severe Alzheimer disease (16).

Results of several studies indicate that cholinesterase inhibition is particularly useful in the management of Alzheimer disease patients whose symptoms are rapidly worsening. A prospective study has shown that patients who respond well to rivastigmine therapy can be identified by clinical features of cholinergic deficiency such as deficits in attention and behavioral symptoms including hallucinations, apathy, anxiety, and psychomotor disturbances (17).

Dual inhibition of acetylcholinesterase and butyrylcholinesterase makes rivastigmine more effective for Alzheimer disease. Its availability as both a transdermal formulation and oral capsule may improve compliance and caregiver satisfaction compared with other cholinesterase inhibitors (21).

Pharmacoeconomics. Pharmacoeconomic analyses indicate that rivastigmine offsets the costs of treatment by delaying cognitive decline and the time to institutionalization in patients with mild to moderate Alzheimer disease.

Adverse effects

The most common adverse effects in clinical trials were asthenia, anorexia, dizziness, nausea, somnolence, and vomiting. Other reported adverse effects included abdominal pain, agitation, confusion, depression, diarrhea, dyspepsia, headache, upper respiratory tract infection, and urinary tract infection. No notable abnormalities in laboratory values were observed.

Patients who take breaks in rivastigmine therapy for longer than about 3 days should resume treatment at the lowest daily dose to reduce the likelihood of severe vomiting. After reinitiating therapy, patients should be titrated back to their maintenance dose. The new recommendation has been incorporated into the warnings, precautions, and dosage and administration sections of the prescribing information of rivastigmine. Pisa syndrome, a state of dystonic muscle contraction with a marked truncal deviation to 1 side, is rarely reported in patients receiving acetylcholinesterase inhibitors, especially rivastigmine. A female patient with Alzheimer disease was observed to have symptoms of Pisa syndrome after continuous use of rivastigmine (9 mg/d) for nearly 2 years (15). The symptoms improved after the dose of rivastigmine was reduced but recurred when the dose was added back to 9 mg/d. Finally, after the dose was decreased 4.5 mg/d, her Pisa syndrome symptoms remitted. Clinicians need to be cautious about the risk of Pisa syndrome when prescribing rivastigmine in a patient with early-onset Alzheimer disease.

In 1 study, approximately 60% of patients who used the rivastigmine patch developed application site reactions such as rash and erythema when the dose was increased to 9 mg, indicating difficulty in increasing the dose to the effective level and in continuing application (22).

References

01: Aguera-Ortiz LF, Ramos-Garcia M, Gobartt AL; en Representacion del Grupo de Investigadores del Estudio SCALEX. [A comparative study of the effectiveness and tolerability of a procedure involving slow dose-escalation of rivastigmine in patients with mild or moderate Alzheimer-type dementia: the SCALEX study. Rev Neurol 2008;46(9):517-24. PMID 18446692
02: Birks JS, Grimley Evans J. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev 2015;4:CD001191.** PMID 25858345
03: Birks J, McGuinness B, Craig D. Rivastigmine for vascular cognitive impairment. Cochrane Database Syst Rev 2013;5:CD004744. PMID 23728651
04: Burns A, Spiegel R, Quarg P. Efficacy of rivastigmine in subjects with moderately severe Alzheimer's disease. Int J Geriatr Psychiatry 2004;19(3):243-9. PMID 15027039
05: Cummings JL, Farlow MR, Meng X, Tekin S, Olin JT. Rivastigmine transdermal patch skin tolerability: results of a 1-year clinical trial in patients with mild-to-moderate Alzheimer's disease. Clin Drug Investig 2010;30(1):41-9. PMID 19995097
06: Drachman DA, Sahakian BJ. Memory and cognitive function in the elderly: a preliminary trial of physostigmine. Arch Neurol 1980;37:674-5. PMID 7425896
07: Farlow MR, Grossberg G, Gauthier S, Meng X, Olin JT. The ACTION study: methodology of a trial to evaluate safety and efficacy of a higher dose rivastigmine transdermal patch in severe Alzheimer's disease. Curr Med Res Opin 2010;26(10):2441-7. PMID 20828359
08: Farlow MR, Grossberg GT, Meng X, Olin J, Somogyi M. Rivastigmine transdermal patch and capsule in Alzheimer's disease: influence of disease stage on response to therapy. Int J Geriatr Psychiatry 2011;26(12):1236-43. PMID 22068922
09: Fayyazi Bordbar MR, Talaei A. Rivastigmine as an effective add-on to standard treatment of veterans with chronic posttraumatic stress disorder: a case series. J Clin Psychopharmacol 2013;33(5):706-9. PMID 23948788
10: Feldman HH, Lane R; Study 304 Group. Rivastigmine: a placebo controlled trial of twice daily and three times daily regimens in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry 2007;78(10):1056-63. PMID 17353259
11: Frampton JE. Rivastigmine transdermal patch 13.3 mg/24 h: a review of its use in the management of mild to moderate Alzheimer's dementia. Drugs Aging 2014;31(8):639-49. PMID 24989628
12: Gauthier S, Robillard A, Cohen S, et al. Real-life effectiveness and tolerability of the rivastigmine transdermal patch in patients with mild-to-moderate Alzheimer's disease: the EMBRACE study. Curr Med Res Opin 2013;29(8):989-1000. PMID 23647369
13: Henderson EJ, Lord SR, Brodie MA, et al. Rivastigmine for gait stability in patients with Parkinson's disease (ReSPonD): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2016;15(3):249-58. PMID 26795874
14: Huolman S, Hämäläinen P, Vorobyev V, et al. The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue. Mult Scler 2011;17(11):1351-61. PMID 21846692
15: Hsu CW, Lee Y, Lee CY, Lin PY. Reversible Pisa syndrome induced by rivastigmine in a patient with early-onset Alzheimer disease. Clin Neuropharmacol 2017;40(3):147-8. PMID 28452906
16: Isaacson RS, Ferris S, Velting DM, Meng X. Cognitive efficacy (SIB) of 13.3 versus 4.6 mg/24 h rivastigmine patch in severe Alzheimer's disease. Am J Alzheimers Dis Other Demen 2016;31(3):270-7.** PMID 26371345
17: Lemstra AW, Kuiper RB, Schmand B, van Gool WA. Identification of responders to rivastigmine: a prospective cohort study. Dement Geriatr Cogn Disord 2008;25(1):60-6. PMID 18033962
18: Mamikonyan E, Xie SX, Melvin E, Weintraub D. Rivastigmine for mild cognitive impairment in Parkinson disease: a placebo-controlled study. Mov Disord 2015;30(7):912-8. PMID 25914281
19: McDonald J, Pourcher E, Nadeau A, Corbeil P. A randomized trial of oral and transdermal rivastigmine for postural instability in Parkinson disease dementia. Clin Neuropharmacol 2018;41(3):87-93. PMID 29537978
20: Muñoz-Moreno JA, Prats A, Moltó J, et al. Transdermal rivastigmine for HIV-associated cognitive impairment: a randomized pilot study. PLoS One 2017;12(8):e0182547. PMID 28854283
21: Nguyen K, Hoffman H, Chakkamparambil B, Grossberg GT. Evaluation of rivastigmine in Alzheimer's disease. Neurodegener Dis Manag 2021;11(1):35-48.** PMID 33198569
22: Osada T, Watanabe N, Asano N, Adachi Y, Yamamura K. Adverse drug events affecting medication persistence with rivastigmine patch application. Patient Prefer Adherence 2018;12:1247-52.** PMID 30050286
23: Park KW, Kim EJ, Han HJ, et al. Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer's dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial. PLoS One 2017;12(8):e0182123. PMID 28786987
24: Pregelj P. Safety and tolerability of rivastigmine transdermal patch formulation in newly diagnosed patients with Alzheimer's dementia in naturalistic conditions. Psychogeriatrics 2012;12(3):165-71. PMID 22994614
25: Ray B, Maloney B, Sambamurti K, et al. Correction: Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer's disease. Transl Psychiatry 2020;10(1):81.** PMID 32123156
26: Scacchi R, Gambina G, Broggio E, Corbo RM. Sex and ESR1 genotype may influence the response to treatment with donepezil and rivastigmine in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2014;29(6):610-5. PMID 24150894
27: Simioni S, Cavassini M, Annoni JM, et al. Rivastigmine for HIV-associated neurocognitive disorders: a randomized crossover pilot study. Neurology 2013;80(6):553-60. PMID 23345635
28: Sobów T, Kłoszewska I, Flirski M, Liberski P. Predictors of long-term treatment effect of rivastigmine in Alzheimer's disease: a role for beta-amyloid plasma levels. Neurol Neurochir Pol 2009;43(6):507-16. PMID 20054753
29: Srinivas NR. Transdermal rivastigmine delivery for Alzheimer disease: amenability of exposure predictions of rivastigmine and metabolite, NAP226-90, by linear regression model using limited samples. Clin Neuropharmacol 2016;39(4):169-77. PMID 27332627
30: Winblad B, Cummings J, Andreasen N, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease--rivastigmine patch versus capsule. Int J Geriatr Psychiatry 2007;22(5):456-67. PMID 17380489

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Rivastigmine

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Rivastigmine

Rivastigmine …

Rivastigmine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
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to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Serotonin syndrome

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

Rivastigmine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Serotonin syndrome

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

This is an article preview.
Start a Free Account
to access the full version.