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  • CLASSES

    Anti-Alzheimer Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Combination acetylcholinesterase inhibitor and NMDA receptor antagonist
    Used for moderate to severe Alzheimer's disease stabilized on donepezil and/or memantine separately; adults with mixed vascular dementia and Alzheimer's disease may experience a small cognitive benefit
    Donepezil has a known risk of QT prolongation; certain conditions, drugs, or foods that raise urine pH may decrease urinary elimination of memantine

    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 and no particular safety issues were identified between the elderly and younger adults. 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. An increase in vagal tone induced by donepezil may produce bradycardia in patients with or without known underlying cardiac conduction abnormalities. Orthostatic hypotension and syncope have been reported infrequently. In addition, donepezil is considered a drug with a known risk of QT prolongation and torsade de pointes (TdP), and geriatric patients may be at increased risk for QT prolongation. According to the Beers Criteria, acetylcholinesterase inhibitors cause bradycardia and are considered potentially inappropriate medications (PIMs) in geriatric patients with an underlying history of syncope and should be avoided in patients whose syncope may be due to bradycardia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the federal Omnibus Budget Reconciliation Act (OBRA) which regulates medication use in residents of long-term care facilities (LTCFs), the continued use of donepezil; memantine should be re-evaluated as the underlying cognitive disorder progresses into advanced stages. Cholinesterase inhibitors should be used cautiously in patients with severe asthma or obstructive pulmonary disease. Cholinesterase inhibitors may cause insomnia, dizziness, nausea, vomiting, diarrhea, anorexia, weight loss, and cardiac conduction abnormalities. 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 / 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: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (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; 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 : (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Acetaminophen; Dextromethorphan: (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; 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.
    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.
    Aclidinium; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    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) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Alfuzosin: (Moderate) Use donepezil with caution in combination with alfuzosin due to the potential for QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Alfuzosin may prolong the QT interval in a dose-dependent manner.
    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.
    Amifampridine: (Moderate) Coaministration of amifampridine and donepezil may increase the risk for adverse reactions due to additive cholinergic effects. Monitor patients closely for new or worsening side effects such as headache, visual disturbances, watery eyes, excessive sweating, shortness of breath, nausea, vomiting, diarrhea, bradycardia, loss of bladder control, confusion, or tremors.
    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.
    Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with donepezil. Amisulpride causes dose- and concentration- dependent QT prolongation. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Amlodipine; Valsartan; 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.
    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; 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.
    Apalutamide: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with apalutamide is necessary. Donepezil is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Apomorphine: (Moderate) Use apomorphine and donepezil together with caution due to the risk of additive QT prolongation. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if donepezil and aprepitant, fosaprepitant are used concurrently and monitor for an increase in donepezil-related adverse effects, including for several days after administration of a multi-day aprepitant regimen. Donepezil is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of donepezil. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Aripiprazole: (Moderate) Use donepezil with caution in combination with aripiprazole. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.
    Armodafinil: (Minor) The elimination of donepezil may be increased by concurrent administration of moderate inducers of CYP3A4, such as modafinil or armodafinil. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Arsenic Trioxide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include arsenic trioxide.
    Artemether; Lumefantrine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Artemether; lumefantrine has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, co-administration of artemether; lumefantrine and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Lumefantrine significantly inhibits CYP2D6, one isoenzyme partially involved in the metabolism of donepezil.
    Articaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Asenapine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include asenapine.
    Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, such as orphenadrine, the functional antagonists of the cholinesterase inhibitors.
    Atazanavir: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil.
    Atazanavir; Cobicistat: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil. (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Atenolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Atenolol; Chlorthalidone: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Atomoxetine: (Moderate) Use donepezil with caution in combination with atomoxetine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of atomoxetine and following overdose.
    Atracurium: (Moderate) A higher atracurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Azithromycin: (Major) Avoid coadministration of azithromycin with donepezil due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    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.
    Betaxolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and donepezil may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Concomitant use of metronidazole and donepezil may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    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; 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.
    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; 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; 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; 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.
    Budesonide; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Budesonide; Glycopyrrolate; Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    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.
    Bupivacaine; Meloxicam: (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.
    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.
    Cabotegravir; Rilpivirine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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) Avoid coadministration of ceritinib with donepezil if possible due to the risk of QT prolongation; plasma concentrations of donepezil may also increase. If concomitant use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Also, monitor for donepezil-related adverse reactions (e.g., GI or cholinergic effects). Donepezil is a CYP3A4 substrate that has had case reports of QT prolongation and torsade de pointes (TdP). Ceritinib is a strong CYP3A4 inhibitor that causes concentration-dependent QT prolongation.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chlorcyclizine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Chloroprocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Chloroquine: (Major) Avoid coadministration of chloroquine with donepezil due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    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; 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.
    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; Ibuprofen; 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: (Moderate) Ciprofloxacin should be used with caution in patients receiving donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during both donepezil and ciprofloxacin therapy.
    Cisapride: (Contraindicated) 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.
    Cisatracurium: (Moderate) A higher cisatracurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Citalopram: (Major) Due to the risk of QT prolongation, citalopram should be avoided in combination with donepezil, if possible. Consider if an alternative to citalopram would be appropriate in dementia patients taking donepezil. If concurrent therapy is considered essential, ECG monitoring is recommended, and do not exceed recommended doses. Citalopram causes dose-dependent QT interval prolongation. Monitor ECG if concurrent use cannot be avoided, and monitor for changes in moods and behaviors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Citalopram has been studied in patients with Alzheimer's disease and clinically significant agitation; patients were receiving donepezil. While citalopram significantly reduced agitation and caregiver distress vs. placebo, the use of citalopram was associated with QTc prolongation and cognitive worsening.
    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.
    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.
    Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with donepezil. QT prolongation and torsade de pointes (TdP) have been reported in patients receiving clofazimine in combination with QT prolonging medications. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Clozapine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than clozapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Clozapine exhibits considerable anticholinergic activity, and is more likely than other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Cobicistat: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Cocaine: (Major) cholinesterase inhibitors reduce the metabolism of cocaine, therefore, prolonging cocaine's effects or increasing the risk of toxicity. It should be taken into consideration that the cholinesterase inhibition caused by echothiophate, demecarium, or isoflurophate may persist for weeks or months after the medication has been discontinued. Additionally, local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Dosage adjustment of the cholinesterase inhibitor may be necessary to control the symptoms of myasthenia gravis.
    Codeine; Phenylephrine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Codeine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Crizotinib: (Major) Avoid coadministration of crizotinib with donepezil due to the risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Cyclobenzaprine: (Moderate) The use of cyclobenzaprine may result in significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Cyproheptadine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dacomitinib: (Moderate) Monitor for increased toxicity of donepezil, such as GI or cholinergic adverse effects, if coadministered with dacomitinib. Coadministration may increase serum concentrations of donepezil. Donepezil is a CYP2D6 substrate; dacomitinib is a strong CYP2D6 inhibitor.
    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 strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Dasatinib: (Moderate) Use donepezil with caution in combination with dasatinib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.
    Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving donepezil as concurrent use may increase the risk for QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. Androgen deprivation therapy (i.e., degarelix) may also prolong the QT/QTc interval.
    Delavirdine: (Minor) Monitor for increased donepezil effects if coadministered with delavirdine. Delavirdine is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Desflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Deutetrabenazine: (Moderate) Use donepezil with caution in combination with deutetrabenazine due to the risk for additive QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range.
    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; Quinidine: (Contraindicated) 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: (Major) Coadministration of dofetilide and donepezil is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. (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: (Moderate) Use donepezil with caution in combination with dolasteron. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram.
    Dolutegravir; 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.
    Dolutegravir; Rilpivirine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (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.
    Dorzolamide; Timolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Doxylamine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Doxylamine; Pyridoxine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Dronedarone: (Contraindicated) The concomitant use of dronedarone with other drugs that prolong the QTc may induce torsade de pointes (TdP) and is contraindicated. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Droperidol: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include droperidol.
    Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with donepezil. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QTc prolongation has been observed with the use of efavirenz. (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.
    Elbasvir; Grazoprevir: (Moderate) Administering donepezil with elbasvir; grazoprevir may result in elevated donepezil plasma concentrations. Donepezil is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eliglustat: (Moderate) Use donepezil with caution in combination with eliglustat. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Empagliflozin; 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.
    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: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    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.
    Encorafenib: (Major) Avoid coadministration of encorafenib and donepezil due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Enflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    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.
    Entrectinib: (Major) Avoid coadministration of entrectinib with donepezil due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Enzalutamide: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with enzalutamide is necessary. Donepezil is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    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.
    Ertugliflozin; 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.
    Erythromycin: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as erythromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Erythromycin; Sulfisoxazole: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Erythromycin has a possible risk for QT prolongation and TdP and use of erythromycin should be used cautiously and with close monitoring with donepezil. In addition, donepezil is partially metabolized by CYP3A4 and coadministration with CYP3A4 inhibitors, such as erythromycin, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Escitalopram: (Moderate) While both escitalopram and donepezil have been reported to cause cases of QT prolongation, the American Psychiatric Association and other experts recommend use of SSRIs including escitalopram in patients with Alzheimer's disease (who are treated with cholinesterase inhibitors) to treat depression, anxiety, or agitation. More study is needed to identify the most effective treatments in this challenging population. If use together is necessary, monitor heart rate and monitor patients for QT prolongation, unusual changes in mood or behaviors, and efficacy of combined treatment.
    Eslicarbazepine: (Moderate) The elimination of donepezil may be increased by concurrent administration of moderate to strong inducers of CYP3A4, such as carbamazepine, eslicarbazepine, or oxcarbazepine. The clinical effect of this interaction on the efficacy of donepezil has not been determined. Observe patients for evidence of reduced donepezil efficacy if these agents are prescribed concurrently.
    Esmolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Etomidate: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Ezogabine: (Moderate) Use donepezil with caution in combination with ezogabine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ezogabine has been associated with QT prolongation.
    Fingolimod: (Moderate) After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsade de pointes (TdP), such as donepezil. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Flecainide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include flecainide.
    Fluconazole: (Moderate) Use donepezil with caution in combination with fluconazole as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluconazole has been associated with QT prolongation and rare cases of TdP.
    Fluoxetine: (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Fluphenazine: (Minor) Administer fluphenazine and donepezil with caution as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, fluphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
    Fluticasone; Salmeterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluticasone; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fluvoxamine: (Moderate) Use donepezil with caution in combination with fluvoxamine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine.
    Formoterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Formoterol; Mometasone: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Fosamprenavir: (Moderate) Fosamprenavir may inhibit the metabolism of other medications that are metabolized via cytochrome P450 3A4, such as donepezil.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as donepezil. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    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.
    Fostemsavir: (Moderate) Use donepezil and fostemsavir together with caution. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, 4 times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.
    Gemifloxacin: (Moderate) Use donepezil with caution in combination with gemifloxacin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Gemifloxacin may prolong the QT interval in some patients. The maximal change in the QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and donepezil together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Gilteritinib: (Moderate) Use caution and monitor for evidence of QT prolongation if concurrent use of gilteritinib and donepezil is necessary. Coadministration has the potential for additive QT prolongation. Gilteritinib has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Glasdegib: (Major) Avoid coadministration of glasdegib with donepezil due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    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) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Granisetron: (Moderate) Use donepezil with caution in combination with granisetron as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Granisetron has been associated with QT prolongation.
    Haloperidol: (Moderate) Use donepezil with caution in combination with haloperidol as concurrent use may increase the risk of QT prolongation and torsade de pointes. QT prolongation and torsade de pointes (TdP) have been observed during haloperidol and donepezil treatment. Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation.
    Halothane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Histrelin: (Major) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    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; 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; 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.
    Hydroxychloroquine: (Major) Avoid coadministration of donepezil and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with donepezil due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Ibutilide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ibutilide.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with donepezil, a CYP3A substrate, as donepezil toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include iloperidone.
    Imatinib: (Moderate) Imatinib, STI-571 is a potent inhibitor of CYP3A4 and 2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Indacaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indacaterol; Glycopyrrolate: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Indinavir: (Moderate) Indinavir inhibits cytochrome P450 3A4 and may interfere with the metabolism of CYP3A4 substrates, such as donepezil. Caution is warranted with coadministration.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with donepezil due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Ipratropium; Albuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Irbesartan; 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.
    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.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with rifampin is necessary. Donepezil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Isoniazid, INH; Rifampin: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with rifampin is necessary. Donepezil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Itraconazole: (Moderate) Use donepezil with caution in combination with itraconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with itraconazole. itraconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Ivosidenib: (Major) Avoid coadministration of ivosidenib with donepezil due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Ketamine: (Moderate) 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: (Moderate) Use donepezil with caution in combination with ketoconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with ketoconazole increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Labetalol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    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.
    Lamivudine; Tenofovir Disoproxil Fumarate: (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.
    Lansoprazole; Amoxicillin; 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.
    Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with donepezil. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Lefamulin: (Major) Avoid coadministration of lefamulin with donepezil as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Lenvatinib: (Major) Avoid coadministration of lenvatinib with donepezil due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of donepezil may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Donepezil is a CYP3A4 substrate. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates is similar to a strong CYP3A4 inhibitor. Concurrent administration with a strong CYP3A inhibitor increased the mean donepezil concentration by 36%. The clinical relevance of this increase in concentration is unknown.
    Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving donepezil. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Levalbuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Levobupivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Levofloxacin: (Moderate) Use donepezil with caution in combination with levofloxacin. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Levofloxacin has also been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin.
    Lidocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used; dosage adjustments of the cholinesterase inhibitor may be necessary. In addition, inhibitors of CYP1A2, such as tacrine, could theoretically reduce lidocaine metabolism and increase the risk of toxicity when given concurrently. Also, rivastigmine is an acetylcholinesterase inhibitor and therefore is likely to exaggerate muscle relaxation under general anesthetics.
    Lidocaine; 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. (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.
    Lisinopril; 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.
    Lithium: (Major) Lithium should be used cautiously and with close monitoring with donepezil as concurrent use may increase the risk of QT prolongation. Lithium has been associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Lofexidine: (Major) Monitor ECG if lofexidine is coadministered with donepezil due to the potential for additive QT prolongation and torsade de pointes (TdP). Lofexidine prolongs the QT interval. In addition, there are postmarketing reports of TdP. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Lonafarnib: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of lonafarnib. The plasma concentrations of donepezil may be elevated when administered concurrently with lonafarnib. Donepezil is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
    Long-acting beta-agonists: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Loperamide: (Moderate) Use donepezil with caution in combination with loperamide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Loperamide; Simethicone: (Moderate) Use donepezil with caution in combination with loperamide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest.
    Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with donepezil due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Losartan; 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.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of donepezil by decreasing its systemic exposure. Donepezil is a primary substrate of CYP3A4. Lumacaftor is a strong inducer of CYP3A.
    Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as donepezil. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.
    Maprotiline: (Moderate) Use donepezil with caution in combination with maprotiline as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Meclizine: (Moderate) Concurrent use of sedating H1-blockers and donepezil should be avoided if possible. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Sedating H1-blockers may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil.
    Mefloquine: (Moderate) Use donepezil with caution in combination with mefloquine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.
    Meperidine; Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Mepivacaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Mepivacaine; Levonordefrin: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Metaproterenol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    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; 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: (Moderate) Methocarbamol may inhibit the effect of cholinesterase inhibitors. Methocarbamol also has sedative properties that may interfere with cognition. Therefore, methocarbamol should be used with caution in patients receiving cholinesterase inhibitors.
    Metoprolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Metoprolol; 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.
    Metronidazole: (Moderate) Concomitant use of metronidazole and donepezil may increase the risk of QT/QTc prolongation and torsade de pointes (TdP) in some patients. Consider taking steps to minimize the risk of QT/QTc interval prolongation and TdP, such as avoidance, electrolyte monitoring and repletion, and ECG monitoring, especially in patients with additional risk factors for TdP.
    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: (Moderate) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include mifepristone. To minimize the risk of QT prolongation, the lowest effective dose of mifepristone should always be used.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 isoenzymes such as donepezil may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Moderate) Use donepezil with caution in combination with mirtazapine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Mirtazapine has been associated with dose-dependent prolongation of the QT interval. Torsade de pointes (TdP) has been reported postmarketing, primarily in overdose or in patients with other risk factors for QT prolongation.
    Mitotane: (Moderate) Use caution if mitotane and donepezil are used concomitantly, and monitor for decreased efficacy of donepezil and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and donepezil is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of donepezil.
    Mivacurium: (Moderate) A higher mivacurium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Mobocertinib: (Major) Concomitant use of mobocertinib and donepezil increases the risk of QT/QTc prolongation and torsade de pointes (TdP). Avoid concomitant use if possible, especially in patients with additional risk factors for TdP. Consider taking steps to minimize the risk for QT/QTc interval prolongation and TdP, such as electrolyte monitoring and repletion and ECG monitoring, if concomitant use is necessary.
    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, Fosnetupitant; Palonosetron: (Moderate) Use caution in administering donepezil with netupitant; palonosetron. coadministration of donepezil with CYP3A4 inhibitors, such as netupitant, may increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    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 coadministration of nilotinib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Donepezil has been associated with QT prolongation and TdP in case reports. Sudden death and QT interval prolongation have occurred in patients who received nilotinib therapy.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs may cause additive pharmacodynamic GI effects with cholinesterase inhibitors, leading to gastrointestinal intolerance. Patients receiving concurrent NSAIDs should be monitored closely for symptoms of active or occult gastrointestinal bleeding. While NSAIDs appear to suppress microglial activity, which in turn may slow inflammatory neurodegenerative processes important for the progression of Alzheimer's disease (AD), there are no clinical data at this time to suggest that NSAIDs alone or as combined therapy with AD agents result in synergistic effects in AD.
    Norfloxacin: (Moderate) Use donepezil with caution in combination with norfloxacin. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Octreotide: (Moderate) Use octreotide with caution in combination with donepezil as concurrent use may increase the risk of QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Ofloxacin: (Moderate) Use donepezil with caution in combination with ofloxacin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Olanzapine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olanzapine; Fluoxetine: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. (Moderate) Monitor for evidence of QT prolongation and increased cholinergic effects if coadministration of donepezil and fluoxetine is necessary. Both donepezil and fluoxetine have been associated with QT prolongation and torsade de pointes (TdP). Additive effects on the QT interval are possible with concurrent use. Additionally, fluoxetine is a potent inhibitor of CYP2D6 and its metabolite is a moderate inhibitor of CYP3A4; donepezil is metabolized by CYPY2D6 and CYP3A4. Concurrent use may lead to increased plasma levels of donepezil. An increased incidence of cholinergic-related side effects may occur.
    Olanzapine; Samidorphan: (Moderate) Consider the use of an antipsychotic with less prominent anticholinergic effects than olanzapine in patients receiving donepezil as concurrent use may decrease donepezil efficacy; additive QT prolongation may also occur. Olanzapine exhibits moderate anticholinergic activity, and is more likely than most other atypical antipsychotics to diminish the therapeutic action of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and exerts its therapeutic effect by improving the availability of acetylcholine. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval.
    Olmesartan; 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.
    Olmesartan; 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.
    Olodaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Ondansetron: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include ondansetron.
    Oritavancin: (Moderate) Donepezil is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of donepezil may be reduced if these drugs are administered concurrently.
    Orphenadrine: (Moderate) The therapeutic benefits of donepezil may be diminished when co-administered with drugs known to exhibit anticholinergic properties, such as orphenadrine, the functional antagonists of the cholinesterase inhibitors.
    Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with donepezil. Osilodrostat is associated with dose-dependent QT prolongation. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
    Osimertinib: (Major) Avoid coadministration of donepezil with osimertinib if possible due to the risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and donepezil concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes (TdP) have been reported with oxaliplatin use in postmarketing experience. Case reports indicate that QT prolongation and TdP can also occur during donepezil therapy.
    Ozanimod: (Major) In general, do not initiate ozanimod in patients taking donepezil due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. If coadministration is necessary and the patient has known risk factors for cardiac disease or arrhythmias, close monitoring is essential.
    Pancuronium: (Moderate) A higher pancuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Paroxetine: (Moderate) Clinical monitoring for drug efficacy, GI or cholinergic effects (e.g., bradycardia or irregular heartbeat), or unusual changes in mood or behavior is recommended during coadministration of donepezil and paroxetine. The plasma concentrations of donepezil may be increased when administered concurrently with paroxetine. Paroxetine is a strong inhibitor of CYP2D6 inhibitor and donepezil undergoes some metabolism by CYP2D6. Paroxetine exhibits anticholinergic effects that may be problematic in the dementia population.
    Pasireotide: (Moderate) Use donepezil with caution in combination with pasireotide as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred with pasireotide at therapeutic and supra-therapeutic doses.
    Pazopanib: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Pazopanib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, pazopanib is a weak inhibitor of CYP3A4, and coadministration of pazopanib and donepezil, a CYP3A4 substrate, may cause an increase in systemic concentrations of donepezil. Use caution when administering these drugs concomitantly.
    Penbutolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Pentamidine: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include pentamidine.
    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) Use donepezil with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Perphenazine; Amitriptyline: (Minor) Use donepezil with caution in combination with perphenazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Perphenazine is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    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: (Contraindicated) 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.
    Pioglitazone; 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.
    Pirbuterol: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Pitolisant: (Major) Avoid coadministration of pitolisant with donepezil as concurrent use may increase the risk of QT prolongation. Pitolisant prolongs the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Ponesimod: (Major) In general, do not initiate ponesimod in patients taking donepezil due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ponesimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ponesimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Posaconazole: (Moderate) Use donepezil with caution in combination with posaconazole as concurrent use may increase the risk of QT prolongation. Posaconazole has been associated with prolongation of the QT interval as well as rare cases of torsade de pointes. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Potassium Bicarbonate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Chloride: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Citrate: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Potassium Citrate; Citric Acid: (Moderate) Increases in urinary pH may decrease elimination of memantine, resulting in drug accumulation and potential toxicity.
    Prilocaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Prilocaine; Epinephrine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Primaquine: (Moderate) Use donepezil with caution in combination with primaquine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Primaquine may cause QT prolongation.
    Procainamide: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include procainamide. (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) Use donepezil with caution in combination with prochlorperazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Prochlorperazine is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    Promethazine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Promethazine; 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. (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Promethazine; Phenylephrine: (Moderate) Use donepezil with caution in combination with promethazine as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also decrease. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Promethazine, a phenothiazine, is associated with a possible risk for QT prolongation. In addition, promethazine exhibits anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity of donepezil.
    Propafenone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Propafenone has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, propafenone inhibits CYP2D6, one of the isoenzymes involved in the metabolism of donepezil. In theory, co-administration of propafenone and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. However, the clinical effect of such an interaction on the response to donepezil has not been determined.
    Propofol: (Moderate) Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with cholinesterase inhibitors in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Propranolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Propranolol; 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.
    Pseudoephedrine; 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.
    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.
    Quinapril; 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.
    Quinidine: (Contraindicated) 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: (Moderate) Use donepezil with caution in combination with ranolazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Ranolazine is associated with dose- and plasma concentration-related increases in the QTc interval. Although there are no studies examining the effects of ranolazine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Relugolix: (Moderate) Use donepezil with caution in combination with relugolix. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Relugolix; Estradiol; Norethindrone acetate: (Moderate) Use donepezil with caution in combination with relugolix. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Androgen deprivation therapy (i.e., relugolix) may also prolong the QT/QTc interval.
    Ribociclib: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with donepezil due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of donepezil may also be increased resulting in increase in treatment-related adverse reactions. Donepezil is a CYP3A4 substrate that has been associated with QT prolongation and TdP in case reports. Ribociclib is a strong CYP3A4 inhibitor that has also been shown to prolong the QT interval in a concentration-dependent manner.
    Rifampin: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with rifampin is necessary. Donepezil is a CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Rifapentine: (Moderate) Monitor for decreased efficacy of donepezil if coadministration with rifapentine is necessary. Donepezil is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Inducers of CYP3A4 could increase the rate of elimination of donepezil.
    Rilpivirine: (Moderate) Use donepezil with caution in combination with rilpivirine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation.
    Risperidone: (Moderate) Use donepezil with caution in combination with risperidone as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Risperidone has been associated with a possible risk for QT prolongation and/or TdP, primarily in the overdose setting.
    Ritonavir: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
    Rocuronium: (Moderate) A higher rocuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Rolapitant: (Major) Use caution if donepezil and rolapitant are used concurrently, and monitor for donepezil-related adverse effects. Donepezil is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant is expected to persist beyond 28 days for an unknown duration. Exposure to another CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in the CYP2D6 substrate concentrations, the last time point measured.
    Romidepsin: (Moderate) Consider monitoring electrolytes and ECGs at baseline and periodically during treatment if romidepsin is administered with donepezil as concurrent use may increase the risk of QT prolongation. Romidepsin has been reported to prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    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) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Saquinavir: (Moderate) Saquinavir may cause elevated plasma concentrations of drugs which are substrates for CYP3A4 isoenzymes, such as donepezil. Patients should be monitored for toxicities associated with donepezil.
    Selpercatinib: (Major) Monitor ECGs more frequently for QT prolongation if coadministration of selpercatinib with donepezil is necessary due to the risk of additive QT prolongation. Concentration-dependent QT prolongation has been observed with selpercatinib therapy. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Sertraline: (Moderate) Sertraline's FDA-approved labeling recommends avoiding concomitant use with drugs known to prolong the QTc interval, such as donepezil; however, the risk of sertraline-induced QT prolongation is generally considered to be low in clinical practice. Its effect on QTc interval is minimal (typically less than 5 msec), and the drug has been used safely in patients with cardiac disease (e.g., recent myocardial infarction, unstable angina, chronic heart failure). If use together is necessary, use caution and monitor patients for QT prolongation. The American Psychiatric Association and other experts recommend the use of SSRIs, including sertraline, to treat patients with Alzheimer's disease (who are receiving cholinesterase inhibitors) for depression, anxiety, or agitation.
    Sevoflurane: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include halogenated anesthetics. In addition, Muscle relaxation produced by succinylcholine can be prolonged when the drug is administered with a cholinesterase inhibitor, like donepezil. If used during surgery, extended respiratory depression could result from prolonged neuromuscular blockade. Other neuromuscular blockers may interact with donepezil in a similar fashion. Cholinesterase inhibitors are therefore also likely to exaggerate muscle relaxation under general anesthetics.
    Short-acting beta-agonists: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of donepezil, which is a CYP3A4 substrate. Monitor patients for adverse effects of donepezil, such as cholinomimetic effects.
    Siponimod: (Major) In general, do not initiate treatment with siponimod in patients receiving donepezil due to the potential for QT prolongation. Consult a cardiologist regarding appropriate monitoring if siponimod use is required. Siponimod therapy prolonged the QT interval at recommended doses in a clinical study. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
    Solifenacin: (Major) Avoid coadministration of solifenacin due to the potential for reduced therapeutic response to donepezil; the risk of QT prolongation and torsade de pointes (TdP) may also be increased. The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic coadministration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Additionally, both drugs are associated with a risk of QT prolongation and TdP. Concurrent use may result in additive effects on the QT interval. (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) Avoid coadministration of sorafenib with donepezil due to the risk of additive QT prolongation. If concomitant use is unavoidable, monitor electrocardiograms and correct electrolyte abnormalities. An interruption or discontinuation of sorafenib therapy may be necessary if QT prolongation occurs. Sorafenib is associated with QTc prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Sotalol: (Major) Monitor for evidence of QT prolongation and torsade de pointes (TdP) if concurrent use of donepezil and sotalol is necessary. Both drugs are associated with a risk of QT prolongation and TdP; these effects may be additive during coadministration. In addition, the increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Spironolactone; 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.
    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.
    Succinylcholine: (Moderate) A synergistic effect may be expected when succinylcholine is given concomitantly with a cholinesterase inhibitor, such as donepezil.
    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: (Moderate) Monitor for evidence of QT prolongation if sunitinib is administered with donepezil. Sunitinib can prolong the QT interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Tacrolimus: (Moderate) Consider ECG and electrolyte monitoring periodically during treatment if tacrolimus is administered with donepezil as concurrent use may increase the risk of QT prolongation. Both tacrolimus and donepezil may prolong the QT interval and cause torsade de pointes (TdP).
    Tamoxifen: (Moderate) Use donepezil with caution in combination with tamoxifen as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses.
    Telaprevir: (Moderate) Close clinical monitoring is advised when administering donepezil with telaprevir due to an increased potential for donepezil-related adverse events. If donepezil dose adjustments are made, re-adjust the dose upon completion of telaprevir treatment. Although this interaction has not been studied, predictions about the interaction can be made based on the metabolic pathway of donepezil. Donepezil is partially metabolized by the hepatic isoenzyme CYP3A4; telaprevir inhibits this isoenzyme. Coadministration may result in elevated donepezil plasma concentrations.
    Telavancin: (Moderate) Use donepezil with caution in combination with telavancin as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Telavancin has been associated with QT prolongation.
    Telithromycin: (Moderate) Use donepezil with caution in combination with telithromycin as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with telithromycin. Both donepezil and telithromycin are associated with QT prolongation and torsade de pointes (TdP). In addition, telithromycin is a strong CYP3A4 inhibitor; donepezil is partially metabolized by CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Telmisartan; 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.
    Terbinafine: (Minor) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as donepezil.
    Terbutaline: (Minor) Use donepezil with caution in combination with short-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tetrabenazine: (Major) Avoid coadministration of tetrabenazine and donepezil due to the potential for QT prolongation. Both tetrabenazine and donepezil have been associated with a risk of QT prolongation; torsade de pointes (TdP) can occur during donepezil therapy. Concurrent use may result in additive effects on the QT interval.
    Tetracaine: (Moderate) Local anesthetics can antagonize the effects of cholinesterase inhibitors by inhibiting neuronal transmission in skeletal muscle, especially if large doses of local anesthetics are used. Also, local anesthetics interfere with the release of acetylcholine. Dosage adjustment of the cholinesterase inhibitor may be necessary.
    Thioridazine: (Contraindicated) Because of the potential for QT prolongation and torsade de pointes (TdP), concurrent use of thioridazine and donepezil is contraindicated. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Both donepezil and thioridazine are considered drugs with a known risk of TdP.
    Timolol: (Moderate) The increase in vagal tone induced by some cholinesterase inhibitors may produce bradycardia, hypotension, or syncope. The vagotonic effect of these drugs may be increased when given with other medications known to cause bradycardia such as beta-blockers. These interactions are pharmacodynamic in nature rather than pharmacokinetic.
    Tiotropium; Olodaterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Tipranavir: (Moderate) In theory, co-administration of tipranavir and donepezil could increase donepezil concentrations, potentially resulting in dose-related toxicity. Tipranavir is a potent inhibitor of CYP3A4 and CYP2D6, the two isoenzymes involved in the metabolism of donepezil. The clinical effect of these interactions on the response to donepezil have not been determined.
    Tolterodine: (Major) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics/medications with anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Antimuscarinic drugs for bladder problems with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include solifenacin and tolterodine. Atropine may be used therapeutically to offset bradycardia in cholinesterase inhibitor overdose.
    Toremifene: (Major) Avoid coadministration of donepezil with toremifene if possible due to the risk of additive QT prolongation. If concomitant use is unavoidable, closely monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Case reports indicate that QT prolongation and torsade de pointes (TdP) can also occur during donepezil therapy.
    Trandolapril; Verapamil: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Trazodone: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with donepezil include trazodone.
    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.
    Triamterene; Hydrochlorothiazide, HCTZ: (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.
    Triclabendazole: (Moderate) Monitor ECGs in patients receiving triclabendazole with donepezil. Transient prolongation of the mean QTc interval was noted on the ECG recordings in dogs administered triclabendazole. Case reports indicate that QT prolongation and torsade de pointes can occur during donepezil therapy.
    Tricyclic antidepressants: (Moderate) Use donepezil with caution in combination with tricyclic antidepressants as concurrent use may increase the risk of QT prolongation; the efficacy of donepezil may also be reduced. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Tricyclic antidepressants with significant anticholinergic activity, such as amitriptyline, imipramine, doxepin, and clomipramine, are more likely to interfere with the therapeutic effect of donepezil than other tricyclics.
    Trifluoperazine: (Minor) Use donepezil with caution in combination with trifluoperazine as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Trifluoperazine is associated with a possible risk for QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with other drugs that have a risk of QT prolongation.
    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.
    Triptorelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., triptorelin) outweigh the potential risks of QT prolongation in patients receiving donepezil as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy may prolong the QT/QTc interval. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy.
    Trospium: (Moderate) 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.
    Tucatinib: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of tucatinib. The plasma concentrations of donepezil may be elevated when administered concurrently with tucatinib. Donepezil is a CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor.
    Umeclidinium; Vilanterol: (Moderate) Use donepezil with caution in combination with long-acting beta-agonists as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Beta-agonists may be associated with adverse cardiovascular effects including QT interval prolongation, usually at higher doses, when associated with hypokalemia, or when used with other drugs known to prolong the QT interval. This risk may be more clinically significant with long-acting beta-agonists as compared to short-acting beta-agonists.
    Valsartan; 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.
    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) Avoid coadministration of vandetanib with donepezil due to an increased risk of QT prolongation and torsade de pointes (TdP). If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes; correct hypocalcemia, hypomagnesemia, and/or hypomagnesemia prior to vandetanib administration. An interruption of vandetanib therapy or dose reduction may be necessary for QT prolongation. Vandetanib can prolong the QT interval in a concentration-dependent manner; TdP and sudden death have been reported in patients receiving vandetanib. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Vardenafil: (Moderate) Use donepezil with caution in combination with vardenafil as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vardenafil is associated with QT prolongation. Both therapeutic and supratherapeutic doses of vardenafil produce an increase in QTc interval.
    Vecuronium: (Moderate) A higher vecuronium dose may be required to achieve neuromuscular block with concomitant use of a cholinesterase inhibitor, such as donepezil.
    Vemurafenib: (Major) Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Vemurafenib has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, concomitant use of vemurafenib and donepezil may result in altered concentrations of donepezil. Vemurafenib is a weak inhibitor of CYP2D6 and an inducer of CYP3A4. Donepezil is a substrate of CYP2D6 and CYP3A4. Use caution and monitor patients for toxicity and efficacy.
    Venlafaxine: (Moderate) Use donepezil with caution in combination with venlafaxine. Both drugs have been associated with a risk of QT prolongation and torsade de pointes.
    Verapamil: (Minor) Verapamil may inhibit the metabolism of donepezil by inhibiting CYP3A4. The clinical effect of this interaction on the response to donepezil has not been determined.
    Voclosporin: (Moderate) Concomitant use of voclosporin and donepezil may increase the risk of QT prolongation. Consider interventions to minimize the risk of progression to torsades de pointes (TdP), such as ECG monitoring and correcting electrolyte abnormalities, particularly in patients with additional risk factors for TdP. Voclosporin has been associated with QT prolongation at supratherapeutic doses. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy.
    Voriconazole: (Moderate) Use donepezil with caution in combination with voriconazole as concurrent use may increase the risk of QT prolongation. Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is also recommended. The plasma concentrations of donepezil may be elevated when administered concurrently with voriconazole. Voriconazole is a strong inhibitor of CYP3A4 inhibitor that has been associated with QT prolongation and rare cases of torsade de pointes. Donepezil is a CYP3A4 substrate; case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Coadministration with another strong CYP3A4 inhibitor increased mean donepezil concentrations by 36%. The clinical significance of this increase is unknown.
    Vorinostat: (Moderate) Use donepezil with caution in combination with vorinostat as concurrent use may increase the risk of QT prolongation. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Vorinostat therapy is associated with a risk of QT prolongation.
    Ziprasidone: (Major) Concomitant use of ziprasidone and donepezil should be avoided due to the potential for additive QT prolongation. Clinical trial data indicate that ziprasidone causes QT prolongation; there are postmarketing reports of torsade de pointes (TdP) in patients with multiple confounding factors. Case reports indicate that QT prolongation and TdP can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP.

    PREGNANCY AND LACTATION

    Pregnancy

    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.