4. Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for ACIs are summarized in Table 3. Only those drug-drug interactions classified as clinical significance level 1 or those considered life threatening which have not yet been classified will be reviewed.

Table 3: Drug-Drug Interactions for ACIs
Target Drug	Interacting Drug	Interaction	Recommendations	Clinical Significance
ACIs	anticholinergics	potential for reduced cholinergic activity with centrally acting anticholinergics; may manifest as reduced activities of daily living but not cognitive function; peripherally acting anticholinergics less likely to attenuate ACI therapeutic effects	monitor for diminished cholinergic effects; choose agents with less centrally acting anticholinergic activity	moderate (CP)
ACIs	cholinergic agents and other cholinesterase inhibitors	enhanced cholinergic/ adverse effects	avoid combination, if possible; if combination needed, monitor for enhanced cholinergic effects; may adjust doses to achieve tolerable clinical effects	major (CP)
ACIs	NSAIDs	potential for additive gastrointestinal effects	monitor for gastrointestinal intolerance and/or bleeding	moderate (CP)
ACIs	beta blockers	increased risk of bradycardia when prescribed concurrently; ACIs may increase vagal tone, resulting in bradycardia, hypotension, and syncope	monitor blood pressure, heart rate during therapy	moderate (CP)
donepezil	QT interval-prolonging medications	adjunctive use may increase risk of QT interval prolongation and torsades de pointes as donepezil has increased risk of QT interval prolongation and torsades de pointes	avoid combined use; if used together, monitor patients for efficacy and cardiovascular adverse outcomes	severe (CP)
donepezil, galantamine	CYP3A4 and CYP2D6 inducers	potential for reduced donepezil serum concentrations and decreased efficacy	monitor for reduced donepezil efficacy	moderate (CP)
donepezil, galantamine	CYP3A4 and CYP2D6 inhibitors	potential for increased donepezil and galantamine serum concentrations	monitor for increased cholinergic effects	galantamine: major; donepezil, galantamine: moderate (CP)
donepezil/ memantine	alkalinizing agents (e.g., select carbonic anhydrase inhibitors, sodium bicarbonate)	memantine clearance reduced by about 80% in alkaline conditions (pH > 8); adjunctive administration with alkalinizing agents may decrease memantine elimination and increase memantine serum levels and potential for increased pharmacologic/ adverse effects	administer drug combination cautiously together; monitor patients for increased pharmacologic/ adverse effects	moderate (CP)
donepezil/ memantine	other drugs excreted by renal tubular secretion (e.g., amiloride, cimetidine, dofetilide, nicotine, quinidine, ranitidine)	memantine eliminated by renal tubular cationic transport; combined administration may result in altered serum levels of both memantine and other drugs excreted by renal tubular secretion due to competition for transport system; elevated dofetilide levels may increase potential for arrhythmias, including torsades de pointes	monitor patient responses, observe for adverse effects or loss of efficacy, and adjust doses as necessary	dofetilide, procainamide, quinidine: major; all other drugs: moderate (CP)
rivastigmine	metoclopramide	combined use may increase risk of extrapyramidal effects as both agents associated with extrapyramidal signs/ symptoms	avoid concurrent use; monitor closely for extrapyramidal effects if combined therapy necessary	major (CP)