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  • CLASSES

    Anti-Alzheimer Combination Products

    DEA CLASS

    Rx

    DESCRIPTION

    Combination acetylcholinesterase inhibitor and NMDA receptor antagonist
    Used for moderate/severe Alzheimer's disease in patients already stabilized on both donepezil and memantine or donepezil alone
    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

    Namzaric

    HOW SUPPLIED

    Namzaric Oral Cap ER: 14-10mg, 21-10mg, 28-10mg, 7-10mg, 7-14-21-28-10mg

    DOSAGE & INDICATIONS

    For the treatment of moderate to severe dementia associated with Alzheimer's disease .
    Oral dosage (extended-release capsule e.g., Namzaric)
    Adults

    The usual target dose is 28 mg/10 mg (containing 28 mg memantine extended-release with 10 mg donepezil) PO once daily in the evening. CONVERTING PATIENTS TO MEMANTINE/DONEPEZIL (NAMZARIC) WHO ARE STABILIZED ON DONEPEZIL BUT NOT CURRENTLY ON MEMANTINE: Initially memantine/donepezil 7 mg/10 mg PO once daily in the evening. Increase after a minimum of 1 week by 7 mg increments of the memantine component, to the recommended maintenance dose of 28 mg/10 mg once daily based on tolerability. FOR PATIENTS CONVERTING TO MEMANTINE/DONEPEZIL (NAMZARIC) AND STABILIZED ON BOTH DONEPEZIL (10 mg PO once daily) AND MEMANTINE (10 mg twice daily or 28 mg extended-release once daily): May convert to memantine/donepezil (Namzaric) 28 mg/10 mg PO once daily in the evening. Start the day following the last dose of memantine and donepezil administered separately. MAXIMUM: memantine/donepezil 28 mg/10 mg PO once daily in the evening.

    MAXIMUM DOSAGE

    Adults

    28 mg/day PO memantine extended-release with 10 mg/day PO donepezil.

    Geriatric

    28 mg/day PO memantine extended-release with 10 mg/day PO donepezil.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Not indicated.

    Neonates

    Not indicated.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed in patients with mild or moderate hepatic impairment. Memantine extended-release/donepezil has not been studied in patients with severe hepatic impairment.

    Renal Impairment

    CrCl 30 mL/min or more: No dosage adjustment is needed.
    CrCl 5 mL/min to 29 mL/min: If stabilized on donepezil 10 mg/day but NOT currently on memantine, initiate with memantine/donepezil (Namzaric) 7 mg/10 mg PO once daily in the evening, then after at least 1 week may increase to the target maintenance dose of memantine/donepezil 14 mg/10 mg PO once daily in the evening. If already stabilized on donepezil 10 mg once daily and memantine (either 5 mg twice daily or 14 mg extended-release once daily), then give memantine/donepezil 14 mg/10 mg PO once daily in the evening.
    CrCl less than 5 mL/min: No quantitative recommendation available.
     
    Hemodialysis
    Specific hemodialysis information is not available.

    ADMINISTRATION

    Oral Administration

    Donepezil; memantine is administered orally.
    Prescribe and administer only to patients titrated and stabilized on the 2 individual drug components.
    The patient should start the combination product the day following the last dose of donepezil and memantine administered separately.

    Oral Solid Formulations

    Administer once daily in the evening.
    May take with or without food.
    Swallow the capsule whole. Alternatively, the capsule may be opened, sprinkled on applesauce, and swallowed without chewing or crushing the contents. When taken this way, the entire contents of the capsule should be consumed; do not divide the dose.
    If a single dose is missed, the next dose should be taken as scheduled. Do not administer double or extra doses.

    STORAGE

    Namzaric:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Donepezil; memantine is contraindicated in patients with a known hypersensitivity to memantine hydrochloride, donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.

    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

    Donepezil; memantine should be used with caution in patients with cardiac disease, sick sinus syndrome, severe cardiac arrhythmias, or cardiac conduction disturbances (e.g., sino-atrial block, AV block). Donepezil, a cholinesterase inhibitor, may increase vagal tone, resulting in bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Hypotension and 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; memantine 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 liver disease may also be at increased risk for QT prolongation. It is advisable to correct electrolyte imbalances prior to donepezil; memantine initiation.

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

    Use donepezil; memantine 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).

    Bladder obstruction

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

    Renal disease, renal failure, renal impairment, urinary tract infection (UTI)

    Use donepezil; memantine with caution in patients with renal disease; dosage adjustments of memantine are required in patients with severe renal impairment (CrCl < 30 ml/min). Data are not available for patients with renal failure on dialysis. Memantine is predominantly eliminated by the kidneys in part by tubular secretion. Conditions, drugs, and/or foods that raise urine pH may decrease urinary elimination of memantine and increase plasma concentrations, potentially increasing the risk of adverse effects, such as dizziness, headache or agitation. Use memantine with caution in patients with conditions that could affect urinary pH such as renal tubular acidosis, urinary tract infection (UTI), and renal failure. Coadministration of drugs that use the same cationic renal tubular secretion system for elimination could potentially result in altered plasma concentrations of memantine or the co-prescribed drug. Carefully monitor patients for response and adverse effects related to each agent.

    Hepatic disease

    Use donepezil; memantine with caution in patients with severe hepatic disease. No dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Donepezil; memantine has not been studied in patients with severe hepatic impairment. Memantine undergoes partial hepatic metabolism, and donepezil clearance was reduced (20%) in 10 patients with stable alcoholic cirrhosis.

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

    Donepezil; memantine 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.

    Seizure disorder, seizures

    Use donepezil; memantine 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

    There are no adequate data on fetal developmental risks associated with the use of donepezil, memantine, or the combination in human pregnancy; therefore, donepezil; memantine should be used in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. During studies in rats, adverse developmental effects (e.g., mortality, decreased body weight, skeletal ossification) were observed in the offspring of rats receiving memantine or donepezil during pregnancy at doses higher than the recommended human dose.

    Breast-feeding

    According to the manufacturer, the developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for donepezil; memantine and any potential adverse effects on the breastfed infant or from the underlying maternal condition. There are no data on the presence of donepezil or memantine in human breast milk, the effects on the breastfed infant, or the effects of donepezil; memantine or its metabolites on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

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

    Surgery

    Donepezil is a cholinesterase inhibitor and therefore is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Patients receiving donepezil; memantine who undergo surgery should be monitored closely for prolonged neuromuscular blockade and respiratory depression.

    Geriatric

    Because Alzheimer's disease is most prevalent in patients 65 years of age and older, clinical trials of donepezil; memantine were naturally focused on this population. During clinical trials for both donepezil and memantine no particular safety issues were identified between the elderly and younger adult populations. However, geriatric patients may be at greater risk for renal impairment and need for memantine dose adjustment due to age-related changes in renal function, concomitant medications, or other risk factors. 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. 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. According to the Beers Criteria, acetylcholinesterase inhibitors, including donepezil, are considered potentially inappropriate medications (PIMs) for use in geriatric patients with syncope and should be avoided in those with syncope due to an increased risk of orthostatic hypotension or bradycardia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to OBRA guidelines, the continued use of both donepezil; memantine for the treatment of a cognitive disorder in residents of a LTCF should be re-evaluated as the underlying disorder progresses into advanced stages. In addition, OBRA guidelines state that cholinesterase inhibitors, such as donepezil, should be used cautiously in patients with severe asthma or obstructive pulmonary disease. Lastly, cholinesterase inhibitors may cause insomnia, dizziness, nausea, vomiting, diarrhea, anorexia, weight loss, and may affect cardiac conduction, particularly in patients who already have a cardiac conduction disorder or who are taking other medications that affect heart rate. Memantine may cause restlessness, distress, dizziness, somnolence, hypertension, headache, hallucinations, or increased confusion.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / Incidence not known
    neuroleptic malignant syndrome / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    bradycardia / Rapid / Incidence not known
    AV block / Early / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    peptic ulcer / Delayed / Incidence not known
    cholecystitis / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    GI bleeding / Delayed / Incidence not known
    renal failure (unspecified) / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hemolytic anemia / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    thrombotic thrombocytopenic purpura (TTP) / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    hypertension / Early / 3.0-4.0
    hallucinations / Early / 3.0-3.0
    depression / Delayed / 2.0-3.0
    hostility / Early / 2.0-3.0
    constipation / Delayed / 3.0-3.0
    atopic dermatitis / Delayed / 3.0-3.0
    hypotension / Rapid / 2.0-2.0
    confusion / Early / 2.0-2.0
    chest pain (unspecified) / Early / 2.0-2.0
    hyperlipidemia / Delayed / 2.0-2.0
    dehydration / Delayed / 2.0-2.0
    urinary incontinence / Early / 2.0-2.0
    QT prolongation / Rapid / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyponatremia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    infection / Delayed / 0-11.0
    diarrhea / Early / 5.0-10.0
    anorexia / Delayed / 8.0-8.0
    vomiting / Early / 2.0-8.0
    headache / Early / 4.0-6.0
    nausea / Early / 6.0-6.0
    dizziness / Early / 2.0-5.0
    insomnia / Early / 5.0-5.0
    ecchymosis / Delayed / 5.0-5.0
    anxiety / Delayed / 4.0-4.0
    influenza / Delayed / 4.0-4.0
    drowsiness / Early / 2.0-3.0
    weight gain / Delayed / 3.0-3.0
    syncope / Early / 2.0-2.0
    emotional lability / Early / 2.0-2.0
    abdominal pain / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    agitation / Early / Incidence not known
    rash (unspecified) / Early / Incidence not known
    muscle cramps / Delayed / Incidence not known
    back pain / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Dolutegravir; Lamivudine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Abacavir; Lamivudine, 3TC: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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.
    Acetazolamide: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Adefovir: (Moderate) Adefovir is eliminated renally by a combination of glomerular filtration and active tubular secretion; coadministration of adefovir dipivoxil with drugs that reduce renal function or compete for active tubular secretion, such as memantine, may decrease adefovir elimination by competing for common renal tubular transport systems; therefore increasing serum concentrations of either adefovir and/or memantine may occur.
    Albuterol: (Minor) 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 the beta-agonists.
    Albuterol; Ipratropium: (Minor) 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 the beta-agonists.
    Alfuzosin: (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 alfuzosin. Based on electrophysiology studies performed by the manufacturer, alfuzosin has a slight effect to prolong the QT interval. The QT prolongation appeared less with alfuzosin 10 mg than with 40 mg. The manufacturer warns that the QT effect of alfuzosin should be considered prior to administering the drug to patients taking other medications known to prolong the QT interval.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Alkalinizing Agents: (Moderate) Urinary alkalinizing agents may decrease the elimination of memantine, resulting in drug accumulation and potential toxicity. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Memantine should be used with caution with drugs known to increase urinary pH.
    Alogliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Amantadine: (Moderate) Amantadine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of amantadine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events. (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, inlcuding amantadine.
    Amiloride: (Minor) Cationic drugs that are eliminated by renal tubular secretion, such as amiloride, may decrease memantine elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of memantine and/or amiloride is recommended.
    Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Cationic drugs that are eliminated by renal tubular secretion, such as amiloride, may decrease memantine elimination by competing for common renal tubular transport systems. Careful patient monitoring and dose adjustment of memantine and/or amiloride is recommended. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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.
    Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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 adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy. (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.
    Apomorphine: (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 apomorphine.
    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) 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 the beta-agonists.
    Aripiprazole: (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 aripiprazole.
    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.
    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 CYP3A4 and 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: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include donepezil.
    Azithromycin: (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 azithromycin.
    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.
    Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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.
    Benzonatate: (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.
    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: (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 metronidazole.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (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 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. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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.
    Bromocriptine: (Moderate) The pharmacologic effects of dopaminergic agents, including the ergot derivative bromocriptine, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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) 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 the 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.
    Canagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Captopril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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.
    Carbonic anhydrase inhibitors: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    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) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and donepezil; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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.
    Cimetidine: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as cimetidine, could result in elevated serum concentrations of one or both drugs.
    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: (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 ciprofloxacin.
    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) Avoid coadministration of citalopram and donepezil due to the potential for QT prolongation and torsade de pointes (TdP). Monitor ECG if concurrent use cannot be avoided. Citalopram is associated with dose-dependent QT 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.
    Citric Acid; Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Citric Acid; Potassium Citrate; Sodium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    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.
    Clobazam: (Moderate) A dosage reduction of CYP2D6 substrates, such as donepezil, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for donepezil-related adverse reactions. It should be noted that because donepezil is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease its clearance.
    Clofarabine: (Moderate) Concomitant use of clofarabine and memantine may result in altered clofarabine levels because both agents are a substrate of OCT2. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OCT2 substrates.
    Clozapine: (Major) Concurrent use of donepezil and clozapine should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and clozapine has a possible risk for QT prolongation and TdP. In addition, 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. Consider the use of an antipsychotic with less prominent anticholinergic effects.
    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 CYP3A4 and CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; 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 CYP3A4 and CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Cobicistat; Elvitegravir; 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 CYP3A4 and CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Codeine; Phenylephrine; Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy.
    Codeine; Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy.
    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) Monitor ECGs for QT prolongation and monitor electrolytes if coadministration of donepezil with crizotinib is necessary. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Crizotinib has also been associated with concentration-dependent QT prolongation.
    Cyclobenzaprine: (Major) Concurrent use of certain muscle relaxants, such as cyclobenzaprine, with donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and cyclobenzaprine has a possible risk for QT prolongation and TdP. In addition, 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.
    Dalfopristin; Quinupristin: (Minor) Monitor for increased donepezil effects if coadministered with dalfopristin; quinupristin. Dalfopristin; quinupristin 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.
    Dapagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    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 CYP3A4 and CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (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. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
    Dasatinib: (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. Dasatinib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, dasatinib is a time-dependent, weak inhibitor of CYP3A4, the primary isoenzyme involved in the metabolism of donepezil. If coadministration is necessary, monitor for donepezil toxicity.
    Daunorubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin (including daunorubicin liposomal), doxorubicin (including doxorubicin liposomal), epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Caution and close monitoring are recommended during concurrent use of donepezil and anthracycline therapy.
    Degarelix: (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 degarelix.
    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: (Major) 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. Donepezil is considered a drug with a known risk of TdP.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Dextromethorphan; Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    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. (Major) Cationic drugs that are eliminated by renal tubular secretion, such as quinidine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or quinidine is recommended to assess for needed dosage adjustments. In selected individuals, quinidine serum concentration monitoring may be appropriate. (Moderate) Dextromethorphan is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of dextromethorphan with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events.
    Digoxin: (Moderate) Digoxin is eliminated by renal tubular secretion and may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or digoxin is recommended to assess for needed dosage adjustments. In selected individuals, digoxin serum concentration monitoring may be appropriate (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: (Severe) Coadministration of dofetilide and donepezil is contraindicated due to the potential for torsade de pointes (TdP). Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP. 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. (Major) Drugs that are actively secreted via cationic secretion (e.g., memantine) should be co-administered with dofetilide with caution since they could increase dofetilide plasma concentrations via potential competition for renal tubular secretion. Competition for renal elimination may increase plasma concentrations of dofetilide and increase the risk of pro-arrhythmias.
    Dolasetron: (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 dolasetron.
    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.
    Doxorubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin (including daunorubicin liposomal), doxorubicin (including doxorubicin liposomal), epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Caution and close monitoring are recommended during concurrent use of donepezil and anthracycline therapy.
    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: (Major) Coadministration of efavirenz and donepezil may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for 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. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates, such as donepezil. 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.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and donepezil may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for 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. In addition, efavirenz induces CYP3A4 and may decrease serum concentrations of drugs metabolized by this enzyme. Caution is recommended when administering efavirenz with CYP3A4 substrates, such as donepezil. 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.
    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: (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 eliglustat.
    Empagliflozin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (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 rilpivirine.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (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 rilpivirine.
    Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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.
    Entecavir: (Moderate) Entecavir is eliminated by active tubular secretion. In theory, coadministration of entecavir with other drugs that are eliminated by active tubular secretion, such as memantine, may increase the serum concentrations of entecavir or memantine due to competition for the drug elimination pathway.
    Epirubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin (including daunorubicin liposomal), doxorubicin (including doxorubicin liposomal), epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Caution and close monitoring are recommended during concurrent use of donepezil and anthracycline therapy.
    Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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: (Major) Use caution and monitor for evidence of QT prolongation and torsade de pointes if coadministration of donepezil and escitalopram is necessary. Both drugs have been associated with QT prolongation and TdP.
    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: (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 ezogabine.
    Fingolimod: (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 fingolimod.
    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: (Severe) Concurrent use of donepezil and fluconazole is considered contraindicated. Donepezil, a CYP3A4 substrate, and fluconazole, a CYP3A4 inhibitor, are both associated with a risk for QT prolongation and TdP. The combined use of two drugs that can cause QT prolongation and TdP, along with a possible increased risk for these effects due to elevated plasma concentrations of donepezil via CYP3A4 inhibition by fluconazole, warrants a contraindication for concurrent use.
    Fluoxetine: (Major) 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: (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. Olanzapine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, 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. Consider the use of an antipsychotic with less prominent anticholinergic effects. (Major) 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. 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. 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) 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 the beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (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 the beta-agonists.
    Fluticasone; Vilanterol: (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 the beta-agonists.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and donepezil. Coadminister with caution. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy and donepezil is considered a drug with a known risk of TdP. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Formoterol: (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 the beta-agonists.
    Formoterol; Mometasone: (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 the 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.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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.
    Gefitinib: (Moderate) Monitor for an increased incidence of donepezil-related adverse effects if gefitinib and donepezil are used concomitantly. At high concentrations, gefitinib is an inhibitor of CYP2D6, which is partially responsible for the metabolism of donepezil. In patients with solid tumors, exposure to metoprolol, another CYP2D6 substrate, was increased by 30% when given on day 15 of gefitinib dosing (500 mg daily); the effect of gefitinib on CYP2D6-dependent drugs is only likely to be clinically relevant when given with CYP2D6 substrates with a narrow therapeutic index or that are individually dose titrated such as donepezil.
    Gemifloxacin: (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 gemifloxacin.
    Gemtuzumab Ozogamicin: (Major) 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. Donepezil is considered a drug with a known risk of TdP.
    Glipizide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Glyburide; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Glycopyrrolate; Formoterol: (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 the beta-agonists.
    Granisetron: (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 granisetron.
    Haloperidol: (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 haloperidol.
    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.
    Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Irbesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Losartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Quinapril: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Telmisartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Triamterene: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as triamterene, could result in elevated serum concentrations of one or both drugs. (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Memantine reduced the bioavailability of hydrochlorothiazide by roughly 20% in a drug interaction study. The clinical significance of this pharmacokinetic interaction, if any, is unknown.
    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: (Major) Donepezil should be used cautiously and with close monitoring with hydroxyzine. Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). 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.
    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.
    Idarubicin: (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. Acute cardiotoxicity can occur during administration of daunorubicin (including daunorubicin liposomal), doxorubicin (including doxorubicin liposomal), epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Caution and close monitoring are recommended during concurrent use of donepezil and anthracycline therapy.
    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) 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 the beta-agonists.
    Indacaterol; Glycopyrrolate: (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 the 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: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil. Both donepezil and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with donepezil (a CYP3A4 substrate) may result in elevated donepezil plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Ivacaftor: (Moderate) Use caution when administering ivacaftor and donepezil concurrently. Ivacaftor is an inhibitor of CYP3A and donepezil is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as donepezil, can theoretically increase donepezil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    Ketamine: (Moderate) Ketamine is a NMDA antagonist and may lead to additive adverse effects if combined with memantine, also an NMDA antagonist. It may be prudent to avoid coadministration of ketamine with memantine. If coadministration cannot be avoided, monitor for increased adverse effects such as agitation, dizziness and other CNS events. (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: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil. Both donepezil and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, ketoconazole has been shown, in vitro, to inhibit the metabolism of donepezil by inhibiting CYP3A4. In a 7-day cross-over study in 18 subjects, ketoconazole (200 mg daily) increased mean donepezil (5 mg daily) concentrations (AUC and Cmax) by 36%. The clinical relevance of this interaction is not known, but elevated donepezil concentrations could result in greater incidence of dose-related toxicity.
    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.
    Lamivudine, 3TC: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as lamivudine, could result in elevated serum concentrations of one or both drugs.
    Lamotrigine: (Minor) Coadministration of memantine and lamotrigine may decrease memantine clearance, resulting in increased plasma concentrations and the potential for adverse events, including vertigo and mental status changes. Lamotrigine is an inhibitor of renal tubular secretion via organic cationic transporter 2 (OCT2) proteins, and memantine is excreted via this route.
    Lapatinib: (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 lapatinib.
    Leuprolide: (Moderate) Donepezil should be used cautiously and with close monitoring with leuprolide. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT 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.
    Leuprolide; Norethindrone: (Moderate) Donepezil should be used cautiously and with close monitoring with leuprolide. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT 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.
    Levalbuterol: (Minor) 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 the 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: (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 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.
    Linagliptin; Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with donepezil. Lithium 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.
    Long-acting beta-agonists: (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 the beta-agonists.
    Loperamide: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like donepezil, should be used cautiously and with close monitoring with loperamide.
    Loperamide; Simethicone: (Major) At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Drugs with a possible risk for QT prolongation and TdP, like donepezil, should be used cautiously and with close monitoring with loperamide.
    Lopinavir; Ritonavir: (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. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
    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. (Moderate) Use caution when administering ivacaftor and donepezil concurrently. Ivacaftor is an inhibitor of CYP3A and donepezil is primarily metabolized by CYP3A. Co-administration of ivacaftor with CYP3A substrates, such as donepezil, can theoretically increase donepezil exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
    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.
    Maprotiline: (Major) Concurrent use of maprotiline and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and maprotiline has a possible risk for QT prolongation and TdP. In addition, 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: (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 mefloquine.
    Meperidine; Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy.
    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) 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 the beta-agonists.
    Metformin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Pioglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Repaglinide: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Rosiglitazone: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Saxagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    Metformin; Sitagliptin: (Moderate) Certain medications used concomitantly with metformin may increase the risk of lactic acidosis. Drugs that are eliminated by renal tubular secretion (e.g., memantine) may decrease metformin elimination by competing for common renal tubular transport systems. It should be noted that in a pharmacokinetic study in which memantine and glyburide; metformin (Glucovance) were coadministered, the pharmacokinetics of memantine, metformin, or glyburide were not altered. Regardless, careful patient monitoring is recommended.
    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.
    Methazolamide: (Moderate) Systemic carbonic anhydrous inhibitors have the potential to increase urine pH, and potentially reduce the renal clearance of memantine. The clearance of memantine is reduced by about 80% under alkaline urine conditions at pH 8. Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Methocarbamol: (Major) The effects of cholinesterase inhibitors may be inhibited by methocarbamol. Therefore, methocarbamol should be used with caution in patients with myasthenia gravis 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: (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 metronidazole.
    Midodrine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as midodrine, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or midodrine is recommended.
    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, RU-486: (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 mifepristone, RU-486.
    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: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and donepezil. Coadminister with caution. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine. The majority of reports have occurred in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with 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.
    Morphine: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    Morphine; Naltrexone: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as morphine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or morphine is recommended to assess for needed dosage adjustments.
    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; 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.
    Nicotine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, like nicotine, could result in elevated serum concentrations of one or both drugs.
    Nilotinib: (Major) Avoid administration of nilotinib with donepezil due to the potential for QT prolongation; increased donepezil-related adverse effects are also possible. Nilotinib therapy should be interrupted if treatment with another drug that prolongs the QT interval is required. If interruption of treatment with nilotinib is not possible, closely monitor for evidence of QT prolongation during concurrent use. Both nilotinib and donepezil may prolong the QT interval; donepezil has also been associated with torsade de pointes. In addition, nilotinib inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. Increased concentrations of donepezil may occur if it is coadministered with nilotinib.
    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: (Major) Use caution if coadministration of donepezil and octreotide is necessary due to the potential for QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of 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.
    Ofloxacin: (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 ofloxacin.
    Olanzapine: (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. Olanzapine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, 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. Consider the use of an antipsychotic with less prominent anticholinergic effects.
    Olodaterol: (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 the beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (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. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
    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) Monitor electrolytes and ECGs for QT prolongation if coadministration of donepezil with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also 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.
    Oxcarbazepine: (Minor) The elimination of donepezil may be increased by concurrent administration of certain in vitro inducers of the hepatic isoenzymes CYP2D6 and CYP3A4 such as oxcarbazepine.
    Paliperidone: (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 paliperidone.
    Paroxetine: (Major) Paroxetine is a potent inhibitor of CYP2D6, and concurrent use with donepezil, a CYP2D6 substrate, may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur. In addition, because donepezil is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events.
    Pasireotide: (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 pasireotide.
    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.
    Pergolide: (Moderate) The pharmacologic effects of pergolide may be enhanced with use of memantine; dosage adjustments of pergolide may be required when memantine is coadministered.
    Perphenazine: (Minor) Administer perphenazine and donepezil with caution. 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. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs that may cause QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Administer perphenazine and donepezil with caution. 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. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs that may cause QT prolongation.
    Phenylephrine; Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy.
    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) 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 the beta-agonists.
    Posaconazole: (Severe) The concurrent use of posaconazole and donepezil is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is a potent inhibitor of CYP3A4, the primary isoenzyme responsible for the metabolism of donepezil. These drugs used in combination may result in elevated donepezil plasma concentrations, causing an increased risk for donepezil-related adverse events, such as QT prolongation. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as donepezil.
    Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Salts: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Pramipexole: (Moderate) The pharmacologic effects of dopaminergic agents, including pramipexole, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    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: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include donepezil.
    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. (Major) Cationic drugs that are eliminated by renal tubular secretion such as procainamide, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or procainamide is recommended to assess for needed dosage adjustments. In selected individuals, procainamide serum concentration monitoring may be appropriate.
    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) Administer prochlorperazine and donepezil with caution. 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. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with drugs that may cause QT prolongation.
    Promethazine: (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. Promethazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil. When concurrent use cannot be avoided, monitor the patient for reduced donepezil efficacy.
    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. (Major) Cationic drugs that are eliminated by renal tubular secretion, such as quinidine, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or quinidine is recommended to assess for needed dosage adjustments. In selected individuals, quinidine serum concentration monitoring may be appropriate.
    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. (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as quinine, could result in elevated serum concentrations of one or both drugs.
    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.
    Ranitidine: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as ranitidine, could result in elevated serum concentrations of one or both drugs.
    Ranolazine: (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. Ranolazine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ranolazine inhibits CYP2D6 and CYP3A4, the two isoenzymes involved in the metabolism of donepezil. The clinical effects of this interaction on the response to donepezil has not been determined. According to the manufacturer for ranolazine, lower doses of CYP2D6 substrates may be required during coadministration with ranolazine. Consider using a lower dose of donepezil during coadministration with ranolazine, and monitor for adverse reactions and clinical response. (Moderate) Coadminister ranolazine and memantine with caution. Memantine is a substrate of the OCT2 transporter. Dosage reduction for metformin, another OCT2 transporter substrate, is recommended by the manufacturer of ranolazine. Coadministration of metformin and ranolazine 1000 mg twice daily results in increased plasma concentrations of metformin. Doses of metformin do not require reduction if coadministered with ranolazine 500 mg twice daily. Reductions in the memantine dose may be necessary.
    Regadenoson: (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 regadenoson.
    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. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and donepezil is a CYP3A4 substrate.
    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. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and donepezil is a CYP3A4 substrate.
    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: (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 rilpivirine.
    Risperidone: (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 risperidone.
    Ritonavir: (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. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
    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 lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Romidepsin: (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 romidepsin.
    Ropinirole: (Moderate) The pharmacologic effects of dopaminergic agents, including dopamine agonists and certain ergot derivatives may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    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.
    Rotigotine: (Moderate) The pharmacologic effects of dopaminergic agents, including dopamine agonists such as rotigotine, may be enhanced with use of memantine; dosage adjustments of dopaminergic agents may be required when memantine is coadministered.
    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) 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 the 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: (Major) Monitor for evidence of QT prolongation if coadministration of donepezil and sertraline is necessary. Both drugs are associated with a risk of QT prolongation and torsade de pointes (TdP). Concurrent use may result in additive effects on the QT interval.
    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) 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 the 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.
    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. (Moderate) The adverse effects of solifenacin may be enhanced with use of memantine; dosage adjustments of the solifenacin may be required when memantine is coadministered.
    Sorafenib: (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 sorafenib.
    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.
    Streptogramins: (Minor) Monitor for increased donepezil effects if coadministered with dalfopristin; quinupristin. Dalfopristin; quinupristin 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (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 sulfamethoxazole; trimethoprim, SMX-TMP, cotrimoxazole. (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    Sunitinib: (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 sunitinib.
    Tacrolimus: (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 tacrolimus.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen with donepezil due to an increased risk of QT prolongation and torsade de pointes (TdP). 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. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    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: (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 telavancin.
    Telithromycin: (Major) Monitor for evidence of QT prolongation as well as increased donepezil effects if coadministered with telithromycin. Both donepezil and telithromycin have been associated with a risk of QT prolongation and torsade de pointes (TdP). Concurrent use may result in additive effects on the QT interval. 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) 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 the 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) 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 the 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) 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 toremifene.
    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.
    Triamterene: (Minor) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as triamterene, could result in elevated serum concentrations of one or both drugs.
    Tricyclic antidepressants: (Major) Concurrent use of tricyclic antidepressants and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and tricyclic antidepressants have a possible risk for QT prolongation and TdP. In addition, 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) 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. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a risk of QT prolongation. Administer these drugs together with caution.
    Trimethoprim: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as trimethoprim, may decrease memantine elimination by competing for common renal tubular transport systems. Although this interaction is theoretical, careful patient monitoring and dose adjustment of memantine and/or trimethoprim is recommended.
    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.
    Trospium: (Moderate) Memantine is excreted in part by renal tubular secretion. Competition of memantine for excretion with other drugs that are also eliminated by tubular secretion, such as trospium, could result in elevated serum concentrations of one or both drugs. (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) 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 the beta-agonists.
    Vancomycin: (Moderate) Cationic drugs that are eliminated by renal tubular secretion, such as vancomycin, may compete with memantine for common renal tubular transport systems, thus possibly decreasing the elimination of one of the drugs. Although theoretical, careful patient monitoring of response to memantine and/or vancomycin is recommended to assess for needed dosage adjustments. In selected individuals, vancomycin serum concentration monitoring may be appropriate.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). 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 also occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose. (Minor) Use caution if coadministration of vandetanib with memantine is necessary, due to a possible increase in memantine-related adverse reactions, including vertigo and mental status changes. Memantine is an OCT2 substrate. Coadministration with vandetanib increased the Cmax and AUC of metformin, another OCT2 substrate, by 50% and 74%, respectively.
    Vardenafil: (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 vardenafil.
    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: (Major) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if coadministration of donepezil and venlafaxine is necessary. Both drugs have been associated with a risk of QT prolongation and TdP. Concurrent use may further increase this risk.
    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: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as donepezil. Both drugs have been associated with QT prolongation; coadministration may increase this risk. Voriconazole has also been associated with rare cases of torsades de pointes, cardiac arrest, and sudden death. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with donepezil (a CYP3A4 substrate) may result in elevated donepezil plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (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 vorinostat.
    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: (Severe) Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes. Ziprasidone is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. 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. Therefore, concurrent use of ziprasidone and donepezil is contraindicated.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on fetal developmental risks associated with the use of donepezil, memantine, or the combination in human pregnancy; therefore, donepezil; memantine should be used in pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus. During studies in rats, adverse developmental effects (e.g., mortality, decreased body weight, skeletal ossification) were observed in the offspring of rats receiving memantine or donepezil during pregnancy at doses higher than the recommended human dose.

    According to the manufacturer, the developmental and health benefits of breast-feeding should be considered along with the clinical need of the mother for donepezil; memantine and any potential adverse effects on the breastfed infant or from the underlying maternal condition. There are no data on the presence of donepezil or memantine in human breast milk, the effects on the breastfed infant, or the effects of donepezil; memantine or its metabolites on milk production. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Donepezil and memantine extended-release are combined in a once-daily dosage form to treat Alzheimer's disease.
    Donepezil: Donepezil selectively inhibits acetylcholinesterase (AchE), the enzyme responsible for the degradation of acetylcholine, thereby improving 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 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.
    Memantine: Memantine is an antagonist at N-methyl-D-aspartate (NMDA) receptors; memantine has a low to moderate affinity for the NMDA receptor. Blockade of NMDA receptors by memantine slows the intracellular calcium accumulation and helps to prevent further nerve damage. A low affinity antagonist to NMDA-type receptors, such as memantine, may prevent excitatory amino acid neurotoxicity without interfering with the physiological actions of glutamate required for memory and learning. Memantine does not affect the release of dopamine or serotonin or alter monoamine oxidase (MAO-A or B) or adenylate cyclase activity. In vitro studies demonstrate that memantine lacks affinity for most serotonin receptor subtypes (except 5HT-3), muscarinic acetycholine, a and ß adrenergic, dopaminergic, histaminic, and glycine receptors. Memantine appears to have antagonist activity at the 5HT-3 receptor, with similar potency to that of the NMDA receptor. Memantine also has partial affinity for nicotinic acetylcholine receptors, with one-sixth to one-tenth the potency (relative to the NMDA receptor). There is no evidence to suggest that the underlying disease process of dementia is affected by administration of memantine.

    PHARMACOKINETICS

    Pharmacokinetics: Donepezil; memantine is administered orally.
    Memantine: Plasma protein binding of memantine is clinically insignificant (45%). Memantine is partially metabolized hepatically; however, the cytochrome P450 (CYP450) system does not have a significant role in memantine metabolism. The half-life of memantine is about 60—80 hours, and 48% of a dose is excreted unchanged in the urine. The remainder is converted primarily to three polar metabolites with minimal NMDA receptor antagonistic activity. Renal clearance involves active renal tubular secretion moderated by pH dependent tubular reabsorption. A total of 74% of a dose is excreted as the parent drug and the N-glucuronide conjugate.
    Donepezil: Donepezil is about 96% bound to plasma proteins, primarily albumins and alpha-1-acid glycoprotein. The drug is extensively metabolized to four major metabolites, two of which are known to be active. Donepezil is metabolized by CYP2D6 (minor) and CYP3A4, and undergoes glucuronidation. Poor metabolizers of CYP2D6 have a 31.5% slower clearance and ultra-rapid metabolizers have a 24% faster clearance of donepezil than extensive metabolizers of CYP2D6. The 6-O-desmethyl donepezil metabolite is thought to inhibit acetylcholinesterase to the same extent as donepezil in vitro and was found in plasma at concentrations equal to about 20% of donepezil. The elimination half-life is about 70 hours. About 57% and 15% of a dose is excreted in urine and feces, respectively, with the remainder unrecovered; 17% of a dose is excreted as unchanged drug.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP3A4
    Donepezil: Donepezil is partially metabolized by CYP3A4 and CYP2D6. In vitro studies have shown little or no inhibition of CYP2B6, CYP2C8 or CYP2C19 by donepezil at clinically relevant concentrations.
    Memantine: CYP-based interactions are not expected. The cytochrome P450 system does not have a significant role in memantine metabolism. However, drugs that alter urinary pH or undergo renal tubular secretion may affect the pharmacokinetics of memantine, or the co-administered drug.

    Oral Route

    Oral administration of the combination of memantine extended-release and donepezil is bioequivalent to individual memantine extended-release and donepezil. Systemic exposure of donepezil; memantine (AUC and Cmax) is similar when administered with food or in a fasted state. In addition, systemic exposure of intact donepezil; memantine is similar to administration of the capsule contents sprinkled on applesauce.
    Extended-release memantine: Memantine is well absorbed after oral administration and has linear pharmacokinetics. After multiple dose administration, peak concentrations of memantine occur at approximately 9 to 12 hours. Absorption is similar when the capsule is taken intact or when the contents are sprinkled on applesauce. In one study comparing 28 mg once daily of extended-release memantine to 10 mg of immediate-release memantine administered twice daily, the Cmax and AUC values were 48% and 33% higher, respectively, for the extended-release regimen. Systemic exposure is not affected by administration with food. However, peak plasma concentrations are achieved earlier with food than on an empty stomach (18 hours vs 25 hours).
    Donepezil: Donepezil is 100% bioavailable following oral administration and has linear pharmacokinetics. Peak plasma concentrations are achieved in 3—4 hours. The rate and extent of absorption are not affected by food. Following multiple dose administration, donepezil accumulates in plasma by 4—7 fold, and steady state is achieved within 15 days.