Background

Rivastigmine is a reversible inhibitor of both the acetylcholinesterase and butyrylcholinesterase enzymes. It is widely used for the treatment of Alzheimer's across its mild, moderate, and severe stages, as well as for the treatment of dementia associated with Parkinson's disease (PDD). Rivastigmine was first approved to be marketed for AD in 1997 in Switzerland, and in the years since has come to be available in some 80 countries worldwide, including the United States, Canada, and Europe, for both AD and PDD.

This drug was originally formulated as a twice-daily oral capsule. It was the first AD therapy to be made available as a skin patch that continuously delivers the drug over 24 hours. The patch is sold in three doses. By way of transdermal absorption, the patch provides steady plasma concentrations of rivastigmine and bypasses first-pass metabolism in the intestine and liver. Because it generates fewer gastrointestinal side effects, it enables patients to receive a higher therapeutic dose (Cummings et al., 2007). Generic versions of different doses of rivastigmine capsules started becoming available in 2010; a generic patch came out in 2015.

Rivastigmine's side effects are consistent with class effects of cholinesterase inhibition. They include most commonly nausea, vomiting, diarrhea, and loss of appetite; less frequently, agitation, depression, dizziness, fatigue/sleeplessness, and others. Side effects tend to be strongest in the beginning weeks, when the dose is titrated up to the therapeutic level, and milder in the maintenance phase. Apart from rare skin sensitivity reactions, the patch is generally better tolerated than the capsules.

Findings

About 75 clinical trials Phase 2 and higher have been registered with rivastigmine. For example, in a six-month North American trial comparing a dose of 6-12 mg/day to 1-4 mg/day and to placebo in 699 patients with mild to moderate AD, rivastigmine capsules showed a modest but dose-dependent benefit on cognition, function, and activities of daily living as measured by the ADAS-cog, the CIBIC-plus, and the Progressive Deterioration Scale (PDS), respectively. Similar results were shown in a European trial in 725 patients with mild to moderate AD that compared 6-12 mg/day to 1-4 mg/day of rivastigmine and placebo, also for six months and using the same outcome measures. Only a quarter to a third of patients had a significant treatment response to rivastigmine capsules (Corey-Bloom et al., 1998; Rösler et al., 1999).

The skin patch formulation was evaluated in the six-month, Phase 3 IDEAL (Investigation of transDermal Exelon in ALzheimer's disease) study in 1,195 patients with mild to moderate AD. Participants received either one of two doses of the rivastigmine patch (9.5 or 17.4 mg over the course of 24 hours), 6 mg twice-daily capsules, or placebo. On efficacy, both patch doses outperformed placebo; the lower-dose patch with a similar effect to that of the capsules, the high-dose patch adding a small benefit on cognition. With the patch, the incidence of gastrointestinal complaints dropped nearly to that of placebo, and two-thirds of caregivers said they preferred the patch. A six-month, 716-patient trial comparing a 4.6 mg/24-hour to a 13.3 mg/24-hour patch reported that the higher dose was more efficacious at comparable tolerability (e.g., Winblad et al., 2007; Grossberg et al., 2011; Farlow et al., 2013). An open-label study in a real-life clinical setting outside of randomized controlled trials reported that 969 patients with mild to moderate AD treated with the rivastigmine patch tended to maintain cognitive and global function over 18 months (Gauthier et al., 2013).

Most double-blind RCTs of rivastigmine lasted three to six months. Some longer-term treatment data are available from open-label extensions or from analyses of clinical observation. For example, one study of 1,998 patients treated for up to five years found that their mean baseline MMSE score of 19.3 declined to above 10 points after five years of rivastigmine treatment, while model-based projections predicted that without treatment it would have declined to below 10 points by three years. Other studies reported clinically meaningful treatment benefits compared with historical controls for two years of treatment (Small et al., 2005; Grossberg et al., 2004).

Overall, the acetylcholinesterase therapies donepezil, rivastigmine, and galantamine are viewed as having similar efficacy and safety, though few side-by-side comparisons exist. One three-month study randomized 111 patients with mild to moderate AD to either donepezil titrated up to 10 mg once daily, or rivastigmine capsules up to 6 mg twice daily. Both regimens led to comparable symptomatic benefits on cognition. Donepezil was better tolerated, though this has since changed with the rivastigmine patch (Wilkinson et al., 2002). A two-year trial comparing rivastigmine to donepezil in 994 patients with moderate to severe AD found that almost half dropped out, most due to gastrointestinal side effects. Those who continued had a similar benefit with either therapy on measures of cognition and behavior, though rivastigmine appeared to perform slightly better on activities of daily living and global function. Subgroup analyses hinted at better results for rivastigmine in patients with a particular butyrylcholinesterase genotype and patients who had symptoms of concomitant Lewy body disease, as well (Bullock et al, 2005). A two-year observational study associated long-term use of rivastigmine with a higher risk of death than long-term use of donepezil (Kazmierski et al., 2018).

Several trials have evaluated rivastigmine for dementia with Lewy bodies and Parkinson's disease dementia. This came up when routine clinical use of cholinesterase inhibitors in dementia patients with symptoms other than typical AD seemed to show a cognitive and clinical benefit in a large minority of such patients (Pakrasi et al., 2003). One multicenter, five-month trial in 120 patients with DLB showed a benefit on apathy, anxiety, delusions, hallucinations, as well as on cognitive performance and attention in the treatment group. About two-thirds of the treated patients had a clinically signifcant response to rivastigmine (McKeith et al., 2000). Based on this and subsequent trials of other cholinesterase inhibitors (see Wang et al, 2014), these medicines are now widely used to treat cognitive and behavioral symptoms in patients with DLB (see Hershey and Coleman-Jackson, 2019).

Hallucinations are a hallmark symptom of DLB and PDD. They represent an area of overlap between these forms of dementia and AD. Retrospective analysis of several trials indicates that AD patients with hallucinations respond better to rivastigmine treatment than those without (Cummings et al., 2010). More broadly, rivastigmine treatment appears to reduce somewhat the concomitant use of antipsychotic medications in people with AD (Scharre et al., 2010). How to manage behavioral symptoms of AD has become a pressing issue since 2005, when the FDA responded with a black-box warning to reports of increased mortality in dementia patients on antipsychotics (see Feb 2011 news; Oct 2005 news).

The EXPRESS (EXelon in PaRkinson's disEaSe dementia Study) trial tested 3 to 12 mg/day of rivastigmine capsules in 541 patients with Parkinson's disease dementia, first for six months in a double-blind and placebo controlled phase, and then in an open-label extension. At six months, treated patients improved modestly on cognition, overall function, and psychiatric symptoms. By 48 weeks, the mean ADAS-cog score for the treatment group remained above baseline, and placebo patients who switched to rivastigmine for the extension phase had a treatment benefit similar to that of the original rivastigmine group during the double-blind trial. Again, patients with hallucinations tended to respond better (e.g., Poewe et al., 2006). Rivastigmine also appeared to improve apathy in patients with advanced PD who did not yet have dementia; this finding is from a small trial conducted in France (Devos et al., 2014). A university-sponsored trial directly assessed the effect of rivastigmine capsules on hallucinations in people with Parkinson’s. It intended to enroll 168 participants with minor visual hallucinations at baseline, with a primary outcome of time to develop psychosis or dementia. Slow recruitment and lack of funding forced this trial to stop at 91 participants; in this study population rivastigmine did not alter the primary endpoint compared to placebo (van Mierlo et al., 2021).

From 2008-2010, Novartis ran an 18-month trial comparing the capsule and patch formulations in 583 patients with mild to moderately severe PDD. This trial assessed whether long-term treatment with rivastigmine led to worsening of motor symptoms while improving cognitive and psychiatric symptoms of PDD. Traditionally, cholinergic agents have been contraindicated for the motor and autonomic aspects of PD. This is in part because anticholinergic drugs, particularly muscarinic receptor antagonists, have been used for the symptomatic treatment of PD since the late 19th century. According to published results, rivastigmine in this trial caused no additional decline in motor function beyond that expected due to natural disease progression. The most common side effects were nausea, vomiting, and tremor, consistent with other studies (Emre et al., 2014).

Gait stability and falls are related to cholinergic deficits in people with Parkinson’s disease. The Phase 2 Rivastigmine for Gait Stability in Parkinson’s Disease (ReSPonD) trial randomized 130 Parkinson’s patients without dementia, who had fallen at least once in the previous year, to 32 weeks of rivastigmine or placebo. Treatment improved the primary outcome of gait variability (Henderson et al., 2016). A Phase 3 trial running through November 2023 is assessing the effect of a rivastigmine patch on the number of falls over one year in 600 patients. The protocol is published (Neumann et al., 2021).

Some studies indicate that rivastigmine may affect cerebrovascular factors influencing dementia. Alzheimer's patients who also have cardiovascular risk factors such as hypertension have been reported to respond better to rivastigmine than patients with more "pure" Alzheimer's disease, and some evidence exists for a treatment benefit of rivastigmine for vascular dementia  (e.g., Erkinjuntti et al., 2003; Farlow et al., 2011; Birks et al., 2013). A more recent study found no difference in the response to rivastigmine in people with either mild or moderate MRI-documented signs of ischemic damage along with Alzheimer’s (Park et al., 2017).

For some years after cholinesterase inhibitor therapies were initially approved for Alzheimer's disease, their small effect created controversy about cost-effectiveness (see Jul 2004 news and extensive commentary). Since then, studies have shown that rivastigmine is modestly effective in the long-term treatment of AD, see above. Pharmacoeconomic studies in the United States and European countries have generally found that cholinesterase inhibitor treatment reduces the cost of care (e.g., Nagy et al., 2011). In the United Kingdom, where this debate had called into question coverage of rivastigmine by this country's universal health care system, NICE in 2011 issued a guidance recommending use of rivastigmine in the treatment of mild to moderate AD (see, e.g. Fillit et al., 1999; Wimo et al., 2003; NICE guidance). In contrast, in May 2018, France’s national health care authority stopped paying for rivastigmine and other cholinesterase inhibitors, claiming an unfavorable risk/benefit ratio for these drugs (see published commentary). 

Post-marketing data on long-term safety continues to accrue. According to worldwide adverse-event monitoring systems, rivastigmine was associated with frequent neuropsychiatric and cardiovascular serious adverse events (Krõger et al., 2015). Rivastigmine use was associated with more deaths than other cholinesterase inhibitors (Ali et al., 2015), partly owing to “patch overdose.” This occurs when patients or caregivers apply a new patch without removing the old one, or apply more than one patch at a time (e.g., Lövborg et al., 2012). Rivastigmine overdose is a medical emergency that can lead to sudden cardiac death. 

More recent analysis of data from the FDA Adverse Events Reporting System (FAERS) revealed an apparently increased risk of pneumonia with rivastigmine compared to other symptomatic medications (Morris et al., 2021). This was possibly related to an increase in reports of difficulty swallowing, also in FAERS (Bu et al., 2022). A different study found a slightly increased risk of pneumonia in people using rivastigmine patches, but not capsules, in an analysis of community dwellers with Alzheimer’s disease in Finland (Lampela et al., 2017). However, a study of U.S. Medicare users noted a lower risk of pneumonia among new users of rivastigmine (Lai et al., 2015).

In other trials, rivastigmine decreased postoperative delirium in older people with cognitive dysfunction (e.g., Youn et al., 2016). It also is suggested to aid recovery after traumatic brain injury, though a recent review calls the evidence for this indication limited (Florentino et al., 2022). 

A small trial in 42 children and adolescents with Down's syndrome found no benefit on measures of cognition, language, and overall function (Spiridigliozzi et al., 2016). Trials for cognitive problems in people with multiple sclerosis were likewise negative (Cotter et al., 2018).

In 2018, Novartis began testing the rivastigmine patch in 102 Alzheimer’s patients with severe dementia. The trial, at nine sites in India, will finish in January 2023. An ongoing trial for progressive supranuclear palsy will also end in 2023.

For a list of rivastigmine trials, see clinicaltrials.gov.