Combining Rivastigmine and Donepezil
No, rivastigmine and donepezil should not be given together. Both are cholinesterase inhibitors with the same mechanism of action, and combining them provides no additional benefit while substantially increasing the risk of cholinergic adverse effects 1, 2.
Why Combination Therapy Is Not Recommended
Using two cholinesterase inhibitors simultaneously is pharmacologically redundant. Both drugs work by inhibiting acetylcholinesterase to increase cholinergic neurotransmission in the brain 3. Combining them does not enhance efficacy but does amplify cholinergic side effects including nausea, vomiting, diarrhea, dizziness, and abdominal pain 1, 3.
Guidelines explicitly recommend using only one cholinesterase inhibitor at a time 1, 2. The American Academy of Family Physicians states that patients who do not respond to one cholinesterase inhibitor may respond to another, indicating the appropriate strategy is switching, not combining 1, 2.
The Correct Approach: Switching Between Agents
If a patient fails to respond adequately to one cholinesterase inhibitor after 6-12 months, switch to a different agent rather than adding a second one 1, 2.
Switching Protocol
Direct switching without washout is safe and well-tolerated. Evidence shows that transitioning from donepezil to rivastigmine within 24-36 hours of discontinuation is safe, with gastrointestinal adverse events occurring in only 8.2% at day 7 and 11.5% at day 28 4.
Start rivastigmine at 1.5 mg twice daily when switching from donepezil, then titrate as tolerated by 1.5 mg twice daily every 4 weeks to a maximum of 6 mg twice daily 1, 4.
Assess response after 6-12 months using physician global assessment, caregiver reports, or neuropsychological testing 1, 2.
When Combination Therapy IS Appropriate
The only evidence-supported combination is adding memantine (an NMDA antagonist) to a cholinesterase inhibitor 5. This represents a different mechanism of action and is appropriate for moderate to severe Alzheimer's disease 1.
In patients who fail rivastigmine monotherapy, adding memantine 5-20 mg/day resulted in 77.9% response rate at 28 weeks, with no significant safety concerns 5.
Memantine works through NMDA receptor antagonism, not cholinesterase inhibition, making this a rational polypharmacy approach 1, 5.
Common Pitfall to Avoid
Do not assume that "more is better" with cholinesterase inhibitors. The modest cognitive benefits seen with these agents (typically 2-4 points on ADAS-Cog) are not enhanced by combining two drugs from the same class 1, 2. The evidence shows no convincing superiority of one cholinesterase inhibitor over another, only differences in dosing schedules and side effect profiles 1, 2.