Sep. 27, 2023
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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.
Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:
• Reversible inhibitors: donepezil, galantamine.
Pharmacodynamics. Rivastigmine is an acetylcholinesterase inhibitor that facilitates cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons.
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.
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 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.
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).
Rivastigmine is contraindicated in patients with known hypersensitivity to rivastigmine, other carbamate derivatives, or to any excipients used in the formulation. Another contraindication is severe liver impairment.
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.
The initial dose is 1.5 mg twice a day. A transdermal patch containing rivastigmine 9 mg (4.6 mg released in 24 hours) or 18 mg (9 mg released in 24 hours) is applied once in 24 hours.
As with other cholinomimetics, care must be taken when using rivastigmine in patients with sick sinus syndrome or cardiac conduction defects (ie, sinoatrial or atrioventricular block). Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.
Anesthesia. As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia.
Pregnancy and lactation. The safety of rivastigmine in human pregnancy has not been established; it should only be given to pregnant women if the potential benefit outweighs the potential risk to the fetus. Rivastigmine is excreted into the milk of animals, but it is not known if rivastigmine is excreted into human milk. Therefore, it is advised that women on rivastigmine do not breast feed.
Pediatric. Children are not recommended to use rivastigmine.
Geriatric. If elderly patients have renal or hepatic impairment, dosing recommendations to titrate according to individual tolerability should be closely followed.
Rivastigmine is minimally metabolized by cytochrome P450 enzymes and has low protein binding; as a result, it is unlikely to interact with other drugs. No pharmacokinetic interactions have been reported between rivastigmine and digoxin, warfarin, diazepam, risperidone, or fluoxetine.
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).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
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