Continuing Education Activity

Rivastigmine is a medication used to manage and treat neurodegenerative disease, specifically dementia, in patients with Alzheimer and Parkinson disease. It is in the cholinesterase inhibitor class of drugs. This activity reviews the indications, action, and contraindications for rivastigmine as a valuable agent in managing dementia (and other disorders when applicable). This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the healthcare team in the management of patients with dementia and related conditions.

Objectives:

• Identify the mechanism of action of rivastigmine.
• Describe the adverse effects and contraindications of rivastigmine.
• Review the appropriate monitoring for potential toxicity of rivastigmine.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance rivastigmine and improve outcomes.

Indications

With the rise in awareness of neurodegenerative diseases at the end of the 20th century, novel drugs were in development to counter the deleterious effects of these diseases. One of the main drugs that came into creation in 1985 was rivastigmine. With its approval by the FDA in 1997, rivastigmine is indicated to treat mild to moderate dementia of the Alzheimer’s type. Its indications also include the treatment of mild to moderate dementia that is associated with Parkinson disease. 

Recent studies have also shown that rivastigmine can improve gait stability to help reduce the risk of falls in patients with Parkinson disease.[1] Additionally, a study done in 2016 has shown that perioperative rivastigmine use can decrease postoperative delirium incidence in older patients with cognitive dysfunction.[2] Researchers have also conducted small studies to see the effectiveness of acetylcholinesterase inhibitors like rivastigmine in hopes of helping cognitive dysfunction in multiple sclerosis patients. Overall, these studies showed no significant benefits over placebo to improve cognitive function.[3]

Multiple studies have also shown that drugs like rivastigmine and other cholinesterase inhibitors can improve cognition in patients with dementia with Lewy bodies based on a computerized cognitive exam. Compared to the placebo group, patients receiving rivastigmine had an improvement of 30% or more, as well as being overall less anxious and fewer episodes of hallucinations.[4]

Mechanism of Action

In the brain, two different cholinesterase enzymes hydrolyze acetylcholine. These two enzymes are acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE is mainly present at the synaptic nerve junctions, as well as areas that have high activity in the cerebral cortex. BuChE is found in the glial cells of the brain and helps mediate cholinergic activity. As humans age, the activity of both of these cholinesterase enzymes increases. In pathologic states like Alzheimer disease and Parkinson disease, the upregulation of cholinesterase enzymes is much higher than normal. Unlike other cholinesterase inhibitors, rivastigmine has been shown reversibly bind to and inhibit both of these enzymes, causing an overall increase in acetylcholine.[5] 

Administration

Rivastigmine is available as oral capsules, oral liquid, and transdermal patches. Capsules are 1.5 mg, 3 mg, 4.5 mg, and 6 mg. The oral solution is 2.0 mg per mL. Transdermal patches are 4.6 mg, 9.5 mg, and 13.3 mg  per 24 hours.

Rivastigmine indications include mild to moderate Alzheimer dementia and dementia associated with Parkinson disease. A mini-mental state examination (MMSE) is performed on patients to see if they qualify for cholinesterase inhibitor therapy. The patient is a candidate for therapy if the MMSE score is between 24 to 26 and 10 to 11 for mild to moderate dementia. Studies show that long-term treatment at a maximum dosage of rivastigmine has the most significant improvement in cognitive performance.[6] Also, discontinuation of acetylcholinesterase inhibitors should be done carefully due to the possible worsening of cognitive impairment.[7]

Oral capsule dosing by indication is as follows:

• Alzheimer disease; mild to moderate dementia: 3 to 6 mg daily by mouth twice daily. Start with 1.5 mg orally twice daily, then increase by 1.5 mg per dose every two weeks per patient tolerated. The maximum dose is 12 mg daily.
• Parkinson disease-associated mild to moderate dementia: 3 to 6 mg daily by mouth twice daily. Start with 1.5 mg orally twice daily, then increase by 1.5 mg per dose every two weeks per patient tolerated. The maximum dose is 12 mg daily.

Doses should be given with food. Clinicians should re-titrate starting at 1.5 mg if treatment interruption exceeds three days.

No renal impairment dosing is necessary. In cases of hepatic impairment, no dose adjustment is necessary for Child-Pugh Class A or B. Child-Pugh Class C dosing is undefined.[8]

Transdermal patch dosing by indications is as follows:

• Alzheimer disease; mild to moderate dementia: Initially apply one 4.6 mg patch daily for four weeks, then increase to a 9.5 mg patch daily for four weeks, then, if necessary, increase to a 13.3 mg patch daily.
• Alzheimer disease; severe dementia: Initially apply one 4.6 mg patch daily for four weeks, then increase to a 9.5 mg patch daily for four weeks, then, if necessary, increase to a 13.3 mg patch daily.
• Parkinson disease-associated mild to moderate dementia: Initially apply one 4.6 mg patch daily for four weeks, then increase to a 9.5 mg patch daily for four weeks, then, if necessary, increase to a 13.3 mg patch daily.

Maximum dosing is 13.3 mg transdermally daily. When converting from oral dosing of 6 to 12 mg daily dosing, start with the 9.5 mg patch. If treatment has been interrupted for more than three days, start with the 4.6 mg patch and titrate.

No renal impairment dosing is necessary. In cases of hepatic impairment, the maximum dose in Child-Pugh Class A or B is 4.6 mg every 24 hours. Child-Pugh Class C dosing is undefined.[8]

Adverse Effects

Adverse effects of rivastigmine have received thorough study as it has been on the market for some time. The main adverse effects associated with the use of rivastigmine are gastrointestinal. The primary symptoms are nausea and vomiting. These acute effects primarily occur during the initial dose-escalation phase of therapy with upward dose titration of the drug to achieve a therapeutic dose. These events can be minimized using a slow titration schedule and taking the medication with food if prescribing an oral formulation. In a study done to analyze the safety and tolerability of cholinesterase inhibitors used to treat Alzheimer dementia, researchers found rivastigmine to be the drug to have the highest rate of gastrointestinal side effects.[9] 

Common adverse effects include extrapyramidal symptoms, sleep disturbances, muscle cramps, and weakness. These issues are less frequent during the maintenance phase of therapy when the dose is not adjusted, but when the drug is being taken for an extended period, central nervous system effects can occur. However, these central nervous system effects are rather rare in rivastigmine and are more common with its counterpart drug, donepezil.[10]  

Studies have shown that using the transdermal patch to deliver rivastigmine is associated with fewer reports of nausea and vomiting.[11] Rivastigmine also has a rare case of angioedema related to its use, although overall very uncommon.[12] While the transdermal route offers decreased rates of gastrointestinal effects, reactions like contact dermatitis are prevalent. Also, allergic reactions to the transdermal patch can manifest as vesicles and edema beyond the boundaries of the patch. 

Long-term use of rivastigmine has also been associated with an increased risk of death compared to patients treated with donepezil.[13]

Contraindications

Relatively few contraindications exist for the usage of rivastigmine in clinical practice. A patient with a history of hypersensitivity to rivastigmine or other drugs with carbamate derivatives should not be prescribed rivastigmine, and other treatment options should merit consideration. Also, severe reactions to other anticholinergic agents should lead clinicians to monitor for similar effects. Patients who have taken anticholinergic medications before and have experienced a cholinergic crisis should also be wary of a potential repeat using rivastigmine.[14]

Other contraindications include a history of allergic contact dermatitis with patch use.

Caution is advised in patients with the following factors:

• Cardiac conduction conditions
• Bradyarrhythmia or sick sinus syndrome
• Chronic obstructive pulmonary disease or asthma
• Bleeding ulcer history or risk
• Seizure risk or history
• Patient weight under 50 kg

Monitoring

Monitoring for this drug should be done primarily by evaluating the patient to see if the therapy results in the desired effect and if there is a clinical improvement from the patient's baseline. Using assessments to assess a patient's cognition can see the patient's progression throughout the treatment. Clinical staff members should all be on the lookout for adverse reactions that can warrant discontinuation or alteration of the route of administration of the drug.

Side effects like gastrointestinal disturbances can warrant a switch to the transdermal form of the drug. Cutaneous side effects also warrant prompt evaluation. Clinical staff members should be aware of the difference between a contact dermatitis reaction and an allergic reaction to the transdermal patch. Contact dermatitis occurs in the spot where the patch was placed and usually resolves. A true allergic reaction to the patch will present as the typical contact dermatitis symptoms in addition to erythema past the boundaries of the patch, as well as the presence of vesicles and/or edema.[14]

Toxicity

Toxicity to the drug, while rare, should be carefully monitored. Common toxicity manifestations include severe gastrointestinal reactions, allergic cutaneous reactions, and central nervous system effects. All cutaneous reactions due to usage of the patch should prompt immediate removal of the patch for at least 48 hours before reapplying in a new area. Therapy should be discontinued if symptoms last longer than 48 hours or a severe cutaneous reaction occurs.

In addition to serious manifestations of common side effects, clinical staff members should always look for cholinergic crises whenever prescribing anticholinergic medications. Classic manifestations of a patient in crisis can be remembered by the mnemonic DUMBELS - diarrhea, urination, miosis, bradycardia, excitability, lacrimation, salivation/excessive sweating before treatment. Patients experiencing a cholinergic crisis should have atropine followed by pralidoxime to reverse the anticholinergic effects of rivastigmine. While the usual treatment of the crisis involves giving atropine before pralidoxime, a case study done in 2009 showed a successful reversal of cholinergic crisis with just pralidoxime without atropine pretreatment.[15]

Enhancing Healthcare Team Outcomes

Patients on rivastigmine, and other anticholinergic medications, should have close follow-ups with the primary clinician taking care of them. Clinicians (MDs, DOs, PAs, NPs) should work closely with nurses to keep a proper follow-up on patients to ensure optimal therapy and be aware of the potential for adverse effects. Clinicians can also work closely with pharmacists to help optimize treatment and prescribe the best regimen to their patients to achieve optimal therapy for their diagnoses; the pharmacist can consult on whether rivastigmine is best suited for the patient at hand or not. Nursing and pharmacy must emphasize the importance of strict compliance to patients, as a lack of compliance can be devastating to therapy and, subsequently, their lives.

Concerns about compliance need to be brought to the prescribing clinician's attention immediately. All members of the interprofessional healthcare team are responsible for providing the best care to their patients and being on the lookout for adverse effects. An interprofessional team employing strategies like those outlined here will result in the best outcomes. [Level 5]