Rivastigmine - Drug Monograph

Introduction

Rivastigmine is a centrally-acting reversible cholinesterase inhibitor approved for the treatment of mild to moderate dementia associated with Alzheimer's disease and Parkinson's disease. As a carbamate derivative, it provides sustained inhibition of acetylcholinesterase and butyrylcholinesterase in the central nervous system, addressing the cholinergic deficit that contributes to cognitive impairment in these neurodegenerative conditions.

Mechanism of Action

Rivastigmine exerts its therapeutic effects through dual inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the brain. Unlike other cholinesterase inhibitors, rivastigmine forms a covalent bond with the active site of cholinesterase enzymes, resulting in prolonged inhibition. This action increases acetylcholine concentrations in cortical and hippocampal regions, enhancing cholinergic neurotransmission. The drug's carbamate structure allows it to preferentially inhibit G1 over G4 molecular forms of AChE, which may contribute to its clinical effects in dementia.

Indications

• Treatment of mild to moderate dementia of the Alzheimer's type
• Treatment of mild to moderate dementia associated with Parkinson's disease

Dosage and Administration

• Oral capsule: 1.5 mg twice daily
• Transdermal patch: 4.6 mg/24 hours

• Increase by 1.5 mg twice daily at minimum 2-week intervals
• Maximum recommended dose: 6 mg twice daily orally or 13.3 mg/24 hours transdermally

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: Use with caution in moderate to severe impairment
• Elderly: No specific dosage adjustment required
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

Contraindications

• Hypersensitivity to rivastigmine, other carbamate derivatives, or components of formulation
• History of application site reactions with transdermal formulation
• Patients with demonstrated hypersensitivity to rivastigmine

Warnings and Precautions

• Gastrointestinal effects: May cause significant nausea, vomiting, anorexia, and weight loss
• Cardiovascular effects: May cause bradycardia and syncope
• Neurological effects: May exacerbate or induce extrapyramidal symptoms
• Pulmonary effects: Use with caution in patients with asthma or COPD
• Transdermal application: Rotate application sites to minimize skin reactions
• Anesthesia: Discontinue prior to surgical procedures requiring anesthesia

Drug Interactions

• Anticholinergic agents: May reduce efficacy of rivastigmine
• Cholinergic agonists: Additive effects and potential toxicity
• Beta-blockers: Increased risk of bradycardia

• Minimal CYP450 interactions due to non-CYP metabolism
• No clinically significant protein binding interactions

Adverse Effects

• Nausea (47%)
• Vomiting (31%)
• Diarrhea (19%)
• Anorexia (17%)
• Dizziness (21%)

• Abdominal pain
• Weight loss
• Headache
• Insomnia
• Fatigue
• Tremor
• Sweating
• Application site reactions (transdermal)

• Severe vomiting leading to dehydration
• Gastrointestinal bleeding
• Seizures
• Extrapyramidal symptoms
• Syncope
• Peptic ulcer disease

Monitoring Parameters

• Complete medical history and physical examination
• Weight and nutritional status assessment
• Cognitive function assessment (MMSE, ADAS-cog)
• Electrocardiogram in patients with cardiac history

• Monthly weight monitoring for first 6 months
• Gastrointestinal symptoms assessment at each visit
• Cognitive and functional assessments every 3-6 months
• Skin evaluation for transdermal patch users
• Vital signs, particularly heart rate

• Clinical response assessment
• Adverse effect profile
• Functional status
• Caregiver burden assessment

Patient Education

• Take with food to minimize gastrointestinal upset
• Maintain adequate fluid intake to prevent dehydration
• Report any significant weight loss or gastrointestinal symptoms
• For transdermal patch: Apply to clean, dry, intact skin on back, upper arm, or chest
• Rotate application sites daily
• Do not apply heat to patch area
• Report any skin reactions or irritation
• Do not stop medication abruptly without medical supervision
• Be aware of potential dizziness and take precautions when changing positions
• Keep regular follow-up appointments for monitoring

• Oral: Take with morning and evening meals
• Transdermal: Apply new patch every 24 hours at same time each day
• Remove old patch before applying new one
• Dispose of used patches carefully

References

1. Grossberg GT, et al. Effectiveness of rivastigmine in Alzheimer's disease and Parkinson's disease dementia. Int J Clin Pract. 2020;74(2):e13456. 2. Birks JS, et al. Rivastigmine for Alzheimer's disease. Cochrane Database Syst Rev. 2015;4:CD001191. 3. FDA Prescribing Information: Exelon (rivastigmine tartrate) capsules and oral solution; Exelon Patch (rivastigmine transdermal system). 4. Cummings J, et al. Role of rivastigmine in Parkinson's disease dementia. Expert Rev Neurother. 2019;19(6):523-533. 5. Winblad B, et al. A 6-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease. Neurology. 2007;69(4 Suppl 1):S14-S22. 6. Emre M, et al. Rivastigmine for dementia associated with Parkinson's disease. N Engl J Med. 2004;351(24):2509-2518. 7. Jann MW, et al. Rivastigmine: the advantages of dual inhibition of acetylcholinesterase and butyrylcholinesterase and its role in subcortical vascular dementia and Parkinson's disease dementia. Clin Interv Aging. 2017;12:697-707.