Drug Interactions between donepezil and PC-CAP

MONITOR: The concomitant use of acetylcholinesterase inhibitors (ACHEIs) (e.g., donepezil, galantamine, benzgalantamine physostigmine, rivastigmine, tacrine) with nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk of gastrointestinal (GI) bleeding. ACHEIs can increase gastric acid secretion due to their cholinergic effects and NSAIDS may increase the risk of GI bleeding and ulceration. In a Swedish retrospective case study of 70,060 patients aged 65 years and older with new prescriptions for both ACHEIs and NSAIDs, 1500 persons were diagnosed with incident peptic ulcer. The results suggested that the risk of peptic ulcer was significantly increased for the combination of ACHEIs and NSAIDs compared to NSAIDs alone. No increased risks were found for the use of ACHEIs alone.


MANAGEMENT: Caution and clinical monitoring are recommended if concomitant use of ACHEIs and NSAIDs is required, especially in patients with a prior history of peptic ulcer disease, the elderly, or debilitated patients. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence gastrointestinal bleeding such as black or tarry stools, bright red blood in vomit, coffee ground like vomit, abdominal pain or cramping, diarrhea, dizziness or lightheadedness, weakness or fatigue and pale skin.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

Coadministration with inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of donepezil, which is primarily metabolized by these isoenzymes. In a 7-day crossover study in 18 healthy volunteers, the potent CYP450 3A4 inhibitor ketoconazole (200 mg once daily) increased the mean peak plasma concentration (Cmax) and systemic exposure (AUC) of donepezil (5 mg once daily) by approximately 36% each. The clinical relevance of these increases is unknown. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of donepezil for at least 28 days after administration of rolapitant.