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  • CLASSES

    Anti-AlzheimerAgents, Cholinesterase Inhibitors

    DEA CLASS

    Rx

    DESCRIPTION

    Piperidine-type reversible cholinesterase (ChE) inhibitor.
    Approved for the symptomatic management of mild to severe Alzheimer's disease; studied off-label for Lewy Body dementia and vascular dementia.
    Donepezil has a known risk of QT prolongation, , risk versus benefit should be determined in patients with risk factors for QT prolongation and Torsade de Pointes (TdP).

    COMMON BRAND NAMES

    Aricept

    HOW SUPPLIED

    Aricept/Donepezil/Donepezil Hydrochloride Oral Tab Orally Dis: 5mg, 10mg
    Aricept/Donepezil/Donepezil Hydrochloride Oral Tab: 5mg, 10mg, 23mg

    DOSAGE & INDICATIONS

    For the treatment of Alzheimer's disease.
    For the treatment of mild to moderate Alzheimer's disease.
    Oral dosage
    Adults

    Initially, 5 mg PO once daily. Upward titration to 10 mg PO once daily should not occur for at least 4 to 6 weeks. The effective dose range is 5 to 10 mg/day PO. There was no statistically consistent benefit of 10 mg/day over 5 mg/day in clinical trials for those with mild to moderate symptoms. However, some patients may gain additional benefit from 10 mg/day. Periodic evaluation after initiation and during continuation of therapy may be helpful in deciding treatment duration (i.e., continue treatment if improvement or stability in functional, cognitive, or behavioral status continues).

    For the treatment of moderate to severe Alzheimer's disease.
    Oral dosage
    Adults

    5 mg PO once daily initially. Upward titration to 10 mg PO once daily should not occur for 4 to 6 weeks. After 10 mg/day for at least 3 months, may further increase to 23 mg PO once daily. Controlled trials suggest that 23 mg/day provides additional benefit over 10 mg/day, although doses ranging from 10 to 23 mg/day are considered effective. Max: 23 mg/day PO. Periodic evaluation after initiation and during continuation of therapy may be helpful in deciding treatment duration (i.e., continue treatment if improvement or stability in functional, cognitive, or behavioral status continues).

    For the treatment of vascular dementia†.
    Oral dosage
    Adults

    Initially give 5 mg PO once daily, with an increase to 10 mg PO once daily after 4 to 6 weeks based upon efficacy and tolerability. Results from 2 large placebo-controlled clinical trials (n = 1,219) in patients with possible or probable vascular dementia showed a beneficial effect in 1 or both of the donepezil groups (5 mg or 10 mg per day dose) on cognitive function, global assessment, and activities of daily living. Dose-related adverse effects included nausea, diarrhea, anorexia, and cramps.

    For the short-term treatment (up to 90 days) of acute cognitive deficits following ischemic stroke†.
    Oral dosage
    Adults

    In one open-label trial, 5 mg PO once daily for 6 weeks followed by titration to 10 mg PO once daily for another 6 weeks improved cognitive function and the ability to perform instrumental activities of daily living (ADL) in patients within 30 days post-stroke. In this trial, donepezil treatment resulted in a significant 14-point increase in functional independence measure (FIM, motor subscale) scores compared to galantamine and historical controls after 12 weeks. In a second open-label study, donepezil was initiated at 5 mg PO once daily within 24 hours of stroke symptom onset, and continued for 30 days, followed by 10 mg PO once daily for 60 days as tolerated, for a total of 90 days of treatment. In this study, 45% of enrolled patients demonstrated favorable outcomes defined as a National Institutes of Health Stroke Scale (NIHSS) score of 0 to 1 indicating minimal long-term deficits at 90-days post-stroke. Furthermore, there was a 70% response rate to donepezil, defined as a Mini-Mental State Examination (MMSE) score greater than 24 at 90 days. Double-blind, placebo-controlled trials are needed to confirm the efficacy of the drug and determine the optimal time and duration of treatment.

    For the treatment of dementia with Lewy bodies†.
    Oral dosage
    Adults

    Results from one 20-week open-label trial indicate that initial treatment with 5 mg PO once daily titrated to 10 mg/day after 4 weeks resulted in significant improvements in the Mini Mental State Examination (MMSE) scores and neuropsychiatric symptoms (NPI-12) scores; however, double-blind, placebo-controlled trials are needed to substantiate these findings.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    23 mg/day PO.

    Elderly

    23 mg/day PO.

    Adolescents

    Not indicated.

    Children

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Although dosage adjustments are not required, patients with hepatic impairment should be closely monitored because donepezil is extensively metabolized in the liver.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Donepezil is administered once daily in the evening, just prior to retiring.
    All dosage forms may be administered with or without food.

    Oral Solid Formulations

    Orally-disintegrating tablets: Place tablet on tongue, allow it to dissolve, then swallow. Instruct the patient to drink some water after the tablet dissolves.
    23 mg Tablets: Swallow whole; do not split, crush, or chew. The manufacturer has noted that crushing or chewing the 23 mg tablet may increase its rate of absorption.

    Oral Liquid Formulations

    Oral solution: Measure dose with a calibrated oral syringe or other calibrated container.

    STORAGE

    Aricept:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Donepezil is contraindicated in patients with a known hypersensitivity to donepezil or to piperidine derivatives.

    Abrupt discontinuation

    Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer's disease and the elderly. Diagnosis should be made according to current guidelines. Therapy with donepezil should only be started if a caregiver is available who will regularly monitor drug intake by the patient. The use of donepezil has not been investigated in patients with other types of dementia, or in patients with other types of memory impairment (e.g., age-related cognitive decline). Avoid abrupt discontinuation of therapy where possible to limit sudden decline in cognitive function or increase in behavioral disturbances. Although patients with Alzheimer's disease and other dementias commonly lose weight, cholinesterase inhibitors, including donepezil, have been associated with weight loss in these patients. During therapy, weight must be monitored.

    Alcoholism, AV block, bradycardia, cardiac arrhythmias, cardiac disease, coronary artery disease, diabetes mellitus, females, heart failure, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, sick sinus syndrome, syncope, thyroid disease

    An increase in vagal tone induced by the cholinomimetic may produce bradycardia or heart block in patients with or without known underlying cardiac conduction abnormalities (e.g., sino-atrial block, AV block) or rhythm disorders (e.g., sick sinus syndrome). Hypotension or syncope may also be exacerbated. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP, and it is recommended to avoid use of donepezil in patients with confirmed or suspected long QT syndrome. Cardiac disease and other factors or conditions that increase the risk of QT prolongation should be taken into consideration prior to donepezil administration including cardiac arrhythmias, heart failure, bradycardia, myocardial infarction, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or concurrent use of drugs that prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes mellitus, thyroid disease, malnutrition, alcoholism, or hepatic disease may also be at increased risk for QT prolongation. It is advisable to correct electrolyte imbalances prior to donepezil initiation.

    Diarrhea, GI bleeding, GI disease, peptic ulcer disease, vomiting

    Use donepezil with caution in patients with GI disease. Cholinesterase inhibitors, such as donepezil, are expected to increase gastric acid secretion due to increased cholinergic activity. Although gastrointestinal effects such as nausea, vomiting, and diarrhea are often mild and transient, patients should be observed closely at the initiation of treatment. Clinical studies of donepezil have shown no increase in the incidence of peptic ulcer disease and GI bleeding relative to placebo; however, patients should be closely monitored for symptoms of active or occult GI bleeding. Special care should be exercised in those at risk for developing ulcers (e.g., those with a history of ulcer disease or those receiving concurrent NSAIDs).

    Hepatic disease

    Donepezil should be used cautiously in patients with hepatic disease. The clearance of donepezil was decreased by 20% in 10 patients with stable alcoholic cirrhosis.

    Asthma, chronic obstructive pulmonary disease (COPD), pulmonary disease

    Donepezil should be used with caution in patients with obstructive-type pulmonary disease. Because of their cholinomimetic actions, cholinesterase inhibitors like donepezil should be prescribed with care to patients with a history of asthma or chronic obstructive pulmonary disease (COPD). Although donepezil is relatively specific for CNS cholinesterase, it does have weak affinity for peripheral cholinesterase which may increase bronchoconstriction and bronchial secretion.

    Bladder obstruction

    Use donepezil with caution in patients predisposed to bladder obstruction. Although not observed in clinical trials of donepezil, cholinomimetics may cause bladder outflow obstruction.

    Seizure disorder, seizures

    Use donepezil with caution in patients with seizure disorder. Cholinomimetics, such as donepezil, are believed to have the potential to cause generalized seizures. Rarely, seizures have been reported with donepezil during post-market use; however, causality has not been established. Seizure activity may also be a manifestation of Alzheimer's disease.

    Pregnancy

    It is not known whether donepezil will cause harm to the fetus during pregnancy or influence reproductive capacity in humans. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal data are available. Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats (late gestation, lactation to weaning) produced an increase in stillbirths and reduced offspring survival at the highest dose. The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m2 basis.

    Breast-feeding

    According to the manufacturer, caution should be used if donepezil is administered to a breast-feeding woman. It is not known whether donepezil is excreted into human breast milk. Safe use during breast-feeding has not been established.

    Children, infants, neonates

    Safety and efficacy of donepezil in neonates, infants, children, and adolescents have not been established. There is no clinical use for this drug in pediatrics.

    Surgery

    Donepezil is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under anesthesia. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade.

    Geriatric

    Because Alzheimer's disease is most prevalent in patients 65 years of age and older, clinical trials of donepezil were naturally focused on this population and no clinically significant differences were observed between geriatric and younger adults in most adverse events. However, geriatric patients may be at greater risk for age-related changes in renal function, concomitant medications, cardiac functioning, or other risk factors. An increase in vagal tone induced by donepezil may produce bradycardia in patients with or without known underlying cardiac conduction abnormalities. Orthostatic hypotension and syncope have been reported infrequently. In addition, donepezil is considered a drug with a known risk of QT prolongation and torsade de pointes (TdP), and geriatric patients may be at increased risk for QT prolongation. According to the Beers Criteria, acetylcholinesterase inhibitors cause bradycardia and are considered potentially inappropriate medications (PIMs) in geriatric patients with an underlying history of syncope and should be avoided in patients whose syncope may be due to bradycardia. According to the federal Omnibus Budget Reconciliation Act (OBRA) which regulates medication use in residents of long-term care facilities (LTCFs), the continued use of donepezil should be re-evaluated as the underlying cognitive disorder progresses into advanced stages. Cholinesterase inhibitors should be used cautiously in patients with severe asthma or obstructive pulmonary disease. Cholinesterase inhibitors may cause insomnia, dizziness, nausea, vomiting, diarrhea, anorexia, weight loss, and cardiac conduction abnormalities.

    ADVERSE REACTIONS

    Severe

    pancreatitis / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    AV block / Early / Incidence not known
    bradycardia / Rapid / Incidence not known
    hemolytic anemia / Delayed / Incidence not known

    Moderate

    atopic dermatitis / Delayed / 3.0-3.0
    hostility / Early / 3.0-3.0
    hallucinations / Early / 3.0-3.0
    depression / Delayed / 2.0-3.0
    hypertension / Early / 3.0-3.0
    urinary incontinence / Early / 1.0-3.0
    dehydration / Delayed / 2.0-2.0
    confusion / Early / 2.0-2.0
    hyperlipidemia / Delayed / 2.0-2.0
    chest pain (unspecified) / Early / 2.0-2.0
    bleeding / Early / 2.0-2.0
    hepatitis / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    QT prolongation / Rapid / Incidence not known

    Mild

    nausea / Early / 6.0-12.0
    infection / Delayed / 11.0-11.0
    diarrhea / Early / 5.0-10.0
    headache / Early / 3.0-10.0
    vomiting / Early / 5.0-9.0
    insomnia / Early / 3.0-9.0
    anorexia / Delayed / 4.0-8.0
    dizziness / Early / 2.0-8.0
    muscle cramps / Delayed / 6.0-6.0
    weight loss / Delayed / 3.0-5.0
    fatigue / Early / 2.0-5.0
    ecchymosis / Delayed / 4.0-5.0
    back pain / Delayed / 3.0-3.0
    abnormal dreams / Early / 3.0-3.0
    arthralgia / Delayed / 2.0-2.0
    asthenia / Delayed / 2.0-2.0
    drowsiness / Early / 2.0-2.0
    emotional lability / Early / 2.0-2.0
    syncope / Early / 2.0-2.0
    increased urinary frequency / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    abdominal pain / Early / Incidence not known
    rash / Early / Incidence not known
    agitation / Early / Incidence not known

    DRUG INTERACTIONS

    Acebutolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Diphenhydramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Aclidinium; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Albuterol; Ipratropium: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Moderate) Use donepezil with caution in combination with alfuzosin due to the potential for QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Alfuzosin may prolong the QT interval in a dose-dependent manner.
    Amantadine: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine.
    Amifampridine: (Moderate) Coaministration of amifampridine and donepezil may increase the risk for adverse reactions due to additive cholinergic effects. Monitor patients closely for new or worsening side effects such as headache, visual disturbances, watery eyes, excessive sweating, shortness of breath, nausea, vomiting, diarrhea, bradycardia, loss of bladder control, confusion, or tremors.
    Amiodarone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Amiodarone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, amiodarone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of amiodarone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Amoxapine: (Major) Amoxapine may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil exerts its therapeutic effect by inhibiting acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Amprenavir: (Moderate) Amprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4, such as donepezil.
    Anagrelide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include anagrelide.
    Anticholinergics: (Moderate) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
    Apalutamide: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with apalutamide is necessary. Donepezil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Apomorphine: (Moderate) Use donepezil with caution in combination with apomorphine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data indicate that QT prolongation is possible with apomorphine administration; the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if donepezil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in donepezil-related adverse effects, including for several days after administration of a multi-day aprepitant regimen. Donepezil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of donepezil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Use donepezil with caution in combination with aripiprazole. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Armodafinil: (Minor) The elimination of donepezil may be increased by concurrent administration of moderate inducers of CYP3A4, such as modafinil or armodafinil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Arsenic Trioxide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include arsenic trioxide.
    Artemether; Lumefantrine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Artemether; lumefantrine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, co-administration of artemether; lumefantrine and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Lumefantrine significantly inhibits CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Articaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Asenapine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include asenapine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, such as orphenadrine, the functional antagonists of the cholinesterase inhibitors.
    Atazanavir: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil.
    Atazanavir; Cobicistat: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil. (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Atenolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Atenolol; Chlorthalidone: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Atomoxetine: (Moderate) Use donepezil with caution in combination with atomoxetine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Azithromycin: (Moderate) Use donepezil with caution in combination with azithromycin; concurrent use increases the risk for QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation and TdP have been spontaneously reported during azithromycin postmarketing surveillance.
    Barbiturates: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP2D6 and CYP3A4, such as barbiturates (including primidone). The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Bedaquiline: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include bedaquiline.
    Bendroflumethiazide; Nadolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Betaxolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Use donepezil with caution in combination with metronidazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Use donepezil with caution in combination with metronidazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Bisoprolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Boceprevir: (Moderate) Observe patients for a potential increase in adverse effects during concurrent administration of donepezil and boceprevir. Donepezil is partially metabolized by CYP3A4. Coadministration with CYP3A4 inhibitors, such as boceprevir, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Bosentan: (Moderate) Bosentan is a potent inducer of CYP3A4 hepatic isoenzymes. Theoretically, bosentan can increase the hepatic clearance of donepezil, a CYP3A4 substrate.
    Brimonidine; Timolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Brompheniramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Brompheniramine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Budesonide; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Bupivacaine Liposomal: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Bupivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Bupivacaine; Lidocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary. (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Buprenorphine: (Major) Buprenorphine should be used cautiously and with close monitoring with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Buprenorphine; Naloxone: (Major) Buprenorphine should be used cautiously and with close monitoring with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Buprenorphine has also been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If these drugs are used together, consider the potential for additive effects on the QT interval.
    Carbamazepine: (Moderate) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and/or CYP3A4, including carbamazepine.
    Carbetapentane; Chlorpheniramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carbinoxamine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Carteolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Ceritinib: (Major) Avoid coadministration of ceritinib with donepezil if possible due to the risk of QT prolongation; plasma concentrations of donepezil may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Also, monitor for donepezil-related adverse reactions (e.g., GI or cholinergic effects). Donepezil is a CYP3A4 substrate that has had case reports of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorcyclizine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chloroprocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as donepezil, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Chlorpheniramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Codeine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Dextromethorphan: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Hydrocodone: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorpromazine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Chlorpromazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, conventional antipsychotics with significant anticholinergic effects, such as chlorpromazine, are more likely than other conventional antipsychotics to diminish the therapeutic action of donepezil, and use of an alternative antipsychotic should be considered. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine.
    Cholinergic agonists: (Major) Cholinergic agonists can cause additive pharmacodynamic effects if used concomitantly with cholinesterase inhibitors. Concurrent use is unlikely to be tolerated by the patient and should be avoided.
    Cinacalcet: (Moderate) In theory, co-administration of cinacalcet and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Cinacalcet is a potent inhibitor of CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Ciprofloxacin: (Moderate) Ciprofloxacin should be used with caution in patients receiving donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during both donepezil and ciprofloxacin therapy.
    Cisapride: (Severe) Coadministration of cisapride and donepezil is contraindicated due to the potential for torsade de pointes (TdP). QT prolongation and ventricular arrhythmias, including TdP, have been reported with cisapride. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Citalopram: (Major) Due to the risk of QT prolongation, citalopram should be avoided in combination with donepezil, if possible. Consider if an alternative to citalopram would be appropriate in dementia patients taking donepezil. If concurrent therapy is considered essential, ECG monitoring is recommended, and do not exceed recommended doses. Citalopram causes dose-dependent QT interval prolongation. Monitor ECG if concurrent use cannot be avoided, and monitor for changes in moods and behaviors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Citalopram has been studied in patients with Alzheimer's disease and clinically significant agitation; patients were receiving donepezil. While citalopram significantly reduced agitation and caregiver distress vs. placebo, the use of citalopram was associated with QTc prolongation and cognitive worsening.
    Clarithromycin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Clarithromycin has a possible risk for QT prolongation and TdP and use of clarithromycin or combinations containing clarithromycin (including amoxicillin; clarithromycin; lansoprazole and amoxicillin; clarithromycin; omeprazole) should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as clarithromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Clemastine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with donepezil. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Clozapine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Cobicistat: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Cocaine: (Major) cholinesterase inhibitors reduce the metabolism of cocaine, therefore, prolonging cocaine's effects or increasing the risk of toxicity. It should be taken into consideration that the cholinesterase inhibition caused by echothiophate, demecarium, or isoflurophate may persist for weeks or months after the medication has been discontinued. Additionally, local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Dosage adjustment of the cholinesterase inhibitor may be necessary to control the symptoms of myasthenia gravis.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Codeine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Conivaptan: (Major) According to the manufacturer, concomitant use of conivaptan, a strong CYP3A4 inhibitor, and CYP3A substrates, such as donepezil, should be avoided. Coadministration of conivaptan with other CYP3A substrates has resulted in increased mean AUC values (2 to 3 times). Theoretically, similar pharmacokinetic effects could be seen with donepezil. Treatment with donepezil may be initiated no sooner than 1 week after completion of conivaptan therapy.
    Crizotinib: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Cyclobenzaprine: (Moderate) The use of cyclobenzaprine may result in significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Cyproheptadine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dacomitinib: (Moderate) Monitor for increased toxicity of donepezil, such as GI or cholinergic adverse effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of donepezil. Donepezil is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    Darunavir; Cobicistat: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Dasatinib: (Moderate) Use donepezil with caution in combination with dasatinib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving donepezil as concurrent use may increase the risk for QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Delavirdine: (Minor) Monitor for increased donepezil effects if coadministered with delavirdine. Delavirdine is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Desflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Deutetrabenazine: (Moderate) For patients taking a deutetrabenazine dosage more than 24 mg/day with donepezil, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Dexamethasone: (Minor) The elimination of donepezil may be increased by concurrent administration of inducers of the hepatic isoenzymes CYP2D6 and CYP3A4, such as dexamethasone.
    Dexchlorpheniramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dextromethorphan; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Dextromethorphan; Quinidine: (Severe) Quinidine and combination products containing quinidine (e.g., dextromethorphan; quinidine) are contraindicated for use with medications that both prolong the QT interval and are CYP2D6 substrates, such as donepezil. Quinidine has QT prolonging actions and has been shown in vitro to inhibit the metabolism of donepezil by CYP2D6 inhibition; therefore, the effects on the QT interval may be increased during concurrent use of these agents. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and the drug is considered a drug with a known risk of TdP.
    Digoxin: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as digoxin. In one study involving multiple doses of galantamine at 24 mg/day with digoxin at a dose of 0.375 mg/day, there was no effect on the pharmacokinetics of digoxin, except one healthy subject was hospitalized due to second and third degree heart block and bradycardia.
    Diltiazem: (Minor) Diltiazem may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Dimenhydrinate: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Diphenhydramine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Diphenhydramine; Ibuprofen: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Diphenhydramine; Naproxen: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Diphenhydramine; Phenylephrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Disopyramide: (Major) Concurrent use of disopyramide and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and disopyramide has a possible risk for QT prolongation and TdP. In addition, disopyramide may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Dofetilide: (Major) Coadministration of dofetilide and donepezil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Dolasetron: (Moderate) Use donepezil with caution in combination with dolasteron. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; Rilpivirine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Dorzolamide; Timolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Doxylamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Doxylamine; Pyridoxine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dronedarone: (Severe) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Droperidol: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include droperidol.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Elbasvir; Grazoprevir: (Moderate) Administering donepezil with elbasvir; grazoprevir may result in elevated donepezil plasma concentrations. Donepezil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Use donepezil with caution in combination with eliglustat. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Encorafenib: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Enflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Entrectinib: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with enzalutamide is necessary. Donepezil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Eribulin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include eribulin.
    Erythromycin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as erythromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Erythromycin; Sulfisoxazole: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as erythromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Escitalopram: (Moderate) While both escitalopram and donepezil have been reported to cause cases of QT prolongation, the American Psychiatric Association and other experts recommend use of SSRIs including escitalopram in patients with Alzheimer's disease (who are treated with cholinesterase inhibitors) to treat depression, anxiety, or agitation. More study is needed to identify the most effective treatments in this challenging population. If use together is necessary, monitor heart rate and monitor patients for QT prolongation, unusual changes in mood or behaviors, and efficacy of combined treatment.
    Eslicarbazepine: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP3A4, such as carbamazepine, eslicarbazepine, or oxcarbazepine. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Esmolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Etomidate: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Ezogabine: (Moderate) Use donepezil with caution in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ezogabine has been associated with QT prolongation.
    Fingolimod: (Moderate) After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP), such as donepezil. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Flecainide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include flecainide.
    Fluconazole: (Moderate) Use donepezil with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluconazole has been associated with QT prolongation and rare cases of TdP.
    Fluoxetine: (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Fluoxetine; Olanzapine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Fluphenazine: (Minor) Administer fluphenazine and donepezil with caution as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Moderate) Use donepezil with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Moderate) Fosamprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4, such as donepezil.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as donepezil. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Fosphenytoin: (Moderate) Fosphenytoin induces hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
    Fospropofol: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Gemifloxacin: (Moderate) Use donepezil with caution in combination with gemifloxacin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and donepezil together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Gilteritinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Glasdegib: (Major) Avoid coadministration of glasdegib with donepezil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Glycopyrrolate; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Granisetron: (Moderate) Use donepezil with caution in combination with granisetron as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Granisetron has been associated with QT prolongation.
    Haloperidol: (Moderate) Use donepezil with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and torsade de pointes. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol and donepezil treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Histrelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Hydrochlorothiazide, HCTZ; Metoprolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Hydrochlorothiazide, HCTZ; Propranolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and donepezil. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with donepezil due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Ibutilide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ibutilide.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with donepezil, a CYP3A substrate, as donepezil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include iloperidone.
    Imatinib: (Moderate) Imatinib, STI-571 is a potent inhibitor of CYP3A4 and 2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Indacaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Moderate) Indinavir inhibits cytochrome P450 3A4 and may interfere with the metabolism of CYP3A4 substrates, such as donepezil. Caution is warranted with coadministration.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with donepezil due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with donepezil may result in increased serum concentrations of donepezil. Donepezil is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isoflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Itraconazole: (Moderate) Use donepezil with caution in combination with itraconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with itraconazole. itraconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with donepezil due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Ketamine: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Ketoconazole: (Moderate) Use donepezil with caution in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with ketoconazole increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Labetalol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with donepezil. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Lefamulin: (Major) Avoid coadministration of lefamulin with donepezil as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of donepezil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Donepezil is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the mean donepezil concentration by 36%. The clinical relevance of this increase in concentration is unknown.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Levalbuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levobupivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Levofloxacin: (Moderate) Use donepezil with caution in combination with levofloxacin. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Levofloxacin has also been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lidocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with donepezil as concurrent use may increase the risk of QT prolongation. Lithium has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with donepezil due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Long-acting beta-agonists: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Use donepezil with caution in combination with loperamide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Use donepezil with caution in combination with loperamide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Lopinavir; Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as donepezil. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Maprotiline: (Moderate) Use donepezil with caution in combination with maprotiline as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Meclizine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Mefloquine: (Moderate) Use donepezil with caution in combination with mefloquine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Mepivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Mepivacaine; Levonordefrin: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Metaproterenol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Methadone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include methadone.
    Methocarbamol: (Moderate) Methocarbamol may inhibit the effect of cholinesterase inhibitors. Methocarbamol also has sedative properties that may interfere with cognition. Therefore, methocarbamol should be used with caution in patients receiving cholinesterase inhibitors.
    Metoprolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Metronidazole: (Moderate) Use donepezil with caution in combination with metronidazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Potential QT prolongation has been reported in limited case reports with metronidazole.
    Midostaurin: (Major) The concomitant use of midostaurin and donepezil may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms (ECG) to monitor the QT interval. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. There have been case reports of QT prolongation and torsade de pointes with donepezil therapy.
    Mifepristone: (Moderate) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include mifepristone. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as donepezil may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) Use donepezil with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Moderate) Use caution if mitotane and donepezil are used concomitantly, and monitor for decreased efficacy of donepezil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and donepezil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of donepezil.
    Modafinil: (Minor) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4 including modafinil.
    Moxifloxacin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include moxifloxacin.
    Nadolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Nebivolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Nebivolol; Valsartan: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Nefazodone: (Minor) Monitor for increased donepezil effects if coadministered with nefazodone. Nefazodone is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Nelfinavir: (Moderate) Nelfinavir may inhibit the metabolism of other substrates of cytochrome P450 3A4 such as donepezil.
    Netupitant, Fosnetupitant; Palonosetron: (Moderate) Use caution in administering donepezil with netupitant; palonosetron. coadministration of donepezil with CYP3A4 inhibitors, such as netupitant, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Neuromuscular blockers: (Major) Cholinesterase inhibitors may be used to reverse the actions of nondepolarizing neuromuscular blockers; however, cholinesterase inhibitors may also prolong the neuromuscular blocking effects if given with depolarizing neuromuscular blockers, as these drugs are metabolized by acetylcholinesterase. In addition, neuromuscular blocking agents can antagonize the effects of the cholinesterase inhibitors; temporary dosage adjustment following surgery may be necessary.
    Nevirapine: (Minor) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4 including nevirapine. The clinical effect of these interactions on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if any of these agents are prescribed concurrently.
    Nilotinib: (Major) Avoid coadministration of nilotinib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Donepezil has been associated with QT prolongation and TdP in case reports. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Norfloxacin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include norfloxacin.
    Octreotide: (Moderate) Use octreotide with caution in combination with donepezil as concurrent use may increase the risk of QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Ofloxacin: (Moderate) Use donepezil with caution in combination with ofloxacin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olodaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Ondansetron: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ondansetron.
    Oritavancin: (Moderate) Donepezil is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of donepezil may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, such as orphenadrine, the functional antagonists of the cholinesterase inhibitors.
    Osimertinib: (Major) Avoid coadministration of donepezil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and donepezil concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience. Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Paroxetine: (Moderate) Clinical monitoring for drug efficacy, GI or cholinergic effects (e.g., bradycardia or irregular heartbeat), or unusual changes in mood or behavior is recommended during coadministration of donepezil and paroxetine. The plasma concentrations of donepezil may be increased when administered concurrently with paroxetine. Paroxetine is a strong inhibitor of CYP2D6 inhibitor and donepezil undergoes some metabolism by CYP2D6. Paroxetine exhibits anticholinergic effects that may be problematic in the dementia population.
    Pasireotide: (Moderate) Use donepezil with caution in combination with pasireotide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Pazopanib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, pazopanib is a weak inhibitor of CYP3A4, and coadministration of pazopanib and donepezil, a CYP3A4 substrate, may cause an increase in systemic concentrations of donepezil. Use caution when administering these drugs concomitantly.
    Penbutolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Pentamidine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include pentamidine.
    Perphenazine: (Minor) Use donepezil with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use donepezil with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Phenylephrine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Phenytoin: (Moderate) Phenytoin induces hepatic microsomal enzymes and may increase the metabolism of other drugs, including donepezil, leading to reduced efficacy of the concomitant medication.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Pimozide: (Severe) Because of the potential for torsade de pointes (TdP), use of donepezil with pimozide is contraindicated. Pimozide is associated with a well-established risk of QT prolongation and TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Pindolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Pirbuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with donepezil as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Posaconazole: (Moderate) Use donepezil with caution in combination with posaconazole as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Prilocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Prilocaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Primaquine: (Moderate) Use donepezil with caution in combination with primaquine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Primaquine may cause QT prolongation.
    Procainamide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include procainamide.
    Procaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Prochlorperazine: (Minor) Use donepezil with caution in combination with prochlorperazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Propafenone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Propofol: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Propranolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Quetiapine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include quetiapine.
    Quinidine: (Severe) Quinidine and combination products containing quinidine (e.g., dextromethorphan; quinidine) are contraindicated for use with medications that both prolong the QT interval and are CYP2D6 substrates, such as donepezil. Quinidine has QT prolonging actions and has been shown in vitro to inhibit the metabolism of donepezil by CYP2D6 inhibition; therefore, the effects on the QT interval may be increased during concurrent use of these agents. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and the drug is considered a drug with a known risk of TdP.
    Quinine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include quinine. In addition, concomitant use of quinine and donepezil may result in increased donepezil concentrations. Quinine is an inhibitor of CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil.
    Ramelteon: (Moderate) Concurrent use of donepezil and ramelteon results in increased ramelteon exposure. If these agents are used together, monitor the patient closely for adverse effects. Use of donepezil 10 mg/day for 26 days and ramelteon as a single 8 mg dose resulted in increased mean AUC and Cmax of ramelteon of approximately 100% and 87%, respectively. No change was observed with regard to the active metabolite, M-II. Clinically meaningful changes in peak and total exposure of donepezil have not been observed.
    Ranolazine: (Moderate) Use donepezil with caution in combination with ranolazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Ribociclib: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Rifamycins: (Moderate) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4, including rifamycins. Observe patients for evidence of reduced donepezil efficacy if rifamycins are prescribed concurrently.
    Rilpivirine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Moderate) Use donepezil with caution in combination with risperidone as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Rolapitant: (Major) Use caution if donepezil and rolapitant are used concurrently, and monitor for donepezil-related adverse effects. Donepezil is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with donepezil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Ropivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine.
    Rufinamide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as donepezil, may occur during concurrent use with rufinamide.
    Salmeterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Moderate) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as donepezil. Patients should be monitored for toxicities associated with donepezil.
    Sertraline: (Moderate) Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval, such as donepezil; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). If use together is necessary, use caution and monitor patients for QT prolongation. The American Psychiatric Association and other experts recommend the use of SSRIs, including sertraline, to treat patients with Alzheimer's disease (who are receiving cholinesterase inhibitors) for depression, anxiety, or agitation.
    Sevoflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Short-acting beta-agonists: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving donepezil due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
    Solifenacin: (Major) Avoid coadministration of solifenacin due to the potential for reduced therapeutic response to donepezil; the risk of QT prolongation and torsade de pointes (TdP) may also be increased. The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic coadministration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Additionally, both drugs are associated with a risk of QT prolongation and TdP. Concurrent use may result in additive effects on the QT interval.
    Sorafenib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of sorafenib with donepezil is necessary; correct any electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib has been associated with QT prolongation. Donepezil is considered a drug with a known risk of torsade de pointes (TdP); case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Sotalol: (Major) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if concurrent use of donepezil and sotalol is necessary. Both drugs are associated with a risk of QT prolongation and TdP; these effects may be additive during coadministration. In addition, the increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    St. John's Wort, Hypericum perforatum: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including donepezil.
    Sunitinib: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with donepezil. Sunitinib can prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with donepezil as concurrent use may increase the risk of QT prolongation. Both tacrolimus and donepezil may prolong the QT interval and cause torsade de pointes (TdP).
    Tamoxifen: (Moderate) Use donepezil with caution in combination with tamoxifen as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering donepezil with telaprevir due to an increased potential for donepezil-related adverse events. If donepezil dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of donepezil. Donepezil is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated donepezil plasma concentrations.
    Telavancin: (Moderate) Use donepezil with caution in combination with telavancin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Telavancin has been associated with QT prolongation.
    Telithromycin: (Moderate) Use donepezil with caution in combination with telithromycin as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with telithromycin. Both donepezil and telithromycin are associated with QT prolongation and torsade de pointes (TdP). In addition, telithromycin is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and donepezil is necessary, as the systemic exposure of donepezil may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of donepezil; consider increasing the dose of donepezil if necessary. Donepezil is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Terbinafine: (Minor) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as donepezil.
    Terbutaline: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine and donepezil due to the potential for QT prolongation. Both tetrabenazine and donepezil have been associated with a risk of QT prolongation; torsade de pointes (TdP) can occur during donepezil therapy. Concurrent use may result in additive effects on the QT interval.
    Tetracaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Thioridazine: (Severe) Because of the potential for QT prolongation and torsade de pointes (TdP), concurrent use of thioridazine and donepezil is contraindicated. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Both donepezil and thioridazine are considered drugs with a known risk of TdP.
    Timolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Tiotropium; Olodaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Moderate) In theory, co-administration of tipranavir and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Tolterodine: (Major) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Antimuscarinic drugs for bladder problems with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include solifenacin and tolterodine. Atropine may be used therapeutically to offset bradycardia in cholinesterase inhibitor overdose.
    Toremifene: (Major) Avoid coadministration of donepezil with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Trandolapril; Verapamil: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Trazodone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include trazodone.
    Tricyclic antidepressants: (Moderate) Use donepezil with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Tricyclic antidepressants with significant anticholinergic activity, such as amitriptyline, imipramine, doxepin, and clomipramine, are more likely to interfere with the therapeutic effect of donepezil than other tricyclics.
    Trifluoperazine: (Minor) Use donepezil with caution in combination with trifluoperazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Triprolidine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Trospium: (Moderate) The therapeutic benefits of the cholinesterase inhibitors for dementia or other neurologic conditions may be diminished during chronic coadministration with antimuscarinics or medications with potent anticholinergic activity. Some of the common selective antimuscarinic drugs for bladder problems, (such as trospium), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia.
    Umeclidinium; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Vandetanib: (Major) Avoid coadministration of vandetanib with donepezil due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Vardenafil: (Moderate) Use donepezil with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vemurafenib: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Vemurafenib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, concomitant use of vemurafenib and donepezil may result in altered concentrations of donepezil. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Donepezil is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venlafaxine: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
    Verapamil: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Voriconazole: (Moderate) Use donepezil with caution in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with voriconazole. Voriconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Vorinostat: (Moderate) Use donepezil with caution in combination with vorinostat as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vorinostat therapy is associated with a risk of QT prolongation.
    Zileuton: (Minor) Zileuton is metabolized by the cytochrome P450 isoenzyme 3A4 and may inhibit CYP3A4 isoenzymes. Zileuton could also potentially compete with other CYP3A4 substrates, such as donepezil.
    Ziprasidone: (Major) Concomitant use of ziprasidone and donepezil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known whether donepezil will cause harm to the fetus during pregnancy or influence reproductive capacity in humans. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal data are available. Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats (late gestation, lactation to weaning) produced an increase in stillbirths and reduced offspring survival at the highest dose. The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m2 basis.

    According to the manufacturer, caution should be used if donepezil is administered to a breast-feeding woman. It is not known whether donepezil is excreted into human breast milk. Safe use during breast-feeding has not been established.

    MECHANISM OF ACTION

    Patients with Alzheimer's disease show behavioral consequences (e.g., decline in memory and learning) that are partially related to cholinergic deficits. CNS structural defects noted on biopsy or postmortem exam include cholinergic lesions in the nuclei projecting from the forebrain nucleus up to the cerebral cortex and the hippocampus, which is the specific region involved with the function of memory. The cholinergic system is known to be important in attentional processing and as a modulator of excitatory amino acid (EAA) neurotransmission. Although there is presently no 'cure' for Alzheimer's disease, therapy with cholinesterase inhibitors is designed to offset the loss of presynaptic cholinergic function and slow the decline of memory and the ability to perform functions of daily living. This mechanism requires that intact cholinergic neurons be present. As Alzheimer's disease progresses, fewer intact cholinergic neurons remain, and cholinesterase inhibitors become less effective. There is considerable evidence indicating that, as in Alzheimer's disease, the central cholinergic system is also impaired in vascular dementia (VaD) and in patients with Alzheimer's disease with cerebrovascular disease ('mixed' dementia), as well as other conditions.
     
    Donepezil selectively inhibits acetylcholinesterase, the enzyme responsible for the destruction of acetylcholine, and improves the availability of acetylcholine. Donepezil binds to AChE via hydrogen bonding and is easily hydrolyzed by body water, thus the duration of enzyme inhibition at the receptor level is very short, and referred to as 'reversible'. However, donepezil's long half-life provides a long duration of drug availability for binding at the receptor sites. Donepezil has much greater affinity for acetylcholinesterase (AChE) in the CNS than for butylcholinesterase (BChE) in the periphery, unlike the organophosphates, acridines, carbamates, physostigmine, and the quaternary ammonium anti-ChEs (ambenonium, neostigmine, pyridostigmine) which have similar affinity for both enzymes. There is no evidence to suggest that the underlying disease process of dementia is affected by administration of donepezil.

    PHARMACOKINETICS

    Donepezil is administered orally. After multiple dosing, it accumulates in plasma by 4 to 7 fold and steady state is reached within 15 days. Donepezil is approximately 96% bound to human plasma proteins, primarily to albumin (about 75%) and alpha-1-acid glycoprotein (about 21%) over the concentration range of 2 to 1000 ng/mL. Donepezil is metabolized to 4 major metabolites, 2 of which are known to be active, and several minor metabolites. Metabolism occurs via hepatic cytochrome P450 (CYP450) isoenzymes CYP2D6 and CYP3A4 and by glucuronidation. Compared to extensive metabolizers of CYP2D6, poor metabolizers have a 31.5% slower clearance and ultra-rapid metabolizers have a 24% faster clearance, suggesting that CYP2D6 has a minor role in the metabolism of donepezil. The 6-O-desmethyl metabolite has been reported to inhibit acetylcholinesterase to the same extent as donepezil in vitro and with plasma concentrations equal to about 20% of donepezil. Approximately 57% and 15% of an administered dose is excreted in the urine and feces, respectively, with 28% of the dose unrecovered. About 17% of a dose is recovered in urine as unchanged drug. Elimination half-life is about 70 hours.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
    Donepezil is partially metabolized by CYP3A4 and CYP2D6. Based upon evaluations of donepezil clearance in CYP2D6 extensive metabolizers, ultra-rapid metabolizers, and poor metabolizers, it is thought that CYP2D6 has a minor role in donepezil metabolism. In vitro studies have shown little or no inhibition of CYP2B6, CYP2C8 or CYP2C19 by donepezil at clinically relevant concentrations.

    Oral Route

    Following oral administration, donepezil is well absorbed with a relative bioavailability of 100%. The rate and extent of absorption of the tablet are not affected by administration with food. The effects of food on the absorption of the orally disintegrating tablet (ODT) have not been formally studied, but are expected to be minimal. Therefore, donepezil may be taken without regard to meals. With the exception of the ODT formulation, donepezil tablets should be swallowed whole. It has been noted by the manufacturer that crushing or chewing the 23 mg tablet may increase its rate of absorption. The kinetics of donepezil are linear over a range of 1 mg to 10 mg given once daily. Peak plasma concentrations of the 10 mg and 23 mg tablet are achieved in about 3 hours and 8 hours, respectively. Peak plasma concentrations following administration of the 23 mg tablet are almost 2-fold higher than those occurring with the 10 mg tablet. Steady state is achieved about 15 days after routine administration.