Pill Identifier App

Donepezil (Systemic)


VA CLASSIFICATION
Primary: CN900

Commonly used brand name(s): Aricept.

Another commonly used name is
E2020 .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Dementia symptoms treatment adjunct—

Indications

Accepted

Dementia, Alzheimer's type, mild to moderate (treatment)—Donepezil is indicated for the treatment of mild to moderate dementia of the Alzheimer's type {01} {03}. There is no evidence that donepezil alters the underlying process that results in dementia, and the effectiveness of donepezil may be decreased as the disease progresses {01} {03}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Chemical group—
    Piperidine derivative {03} {07}.
Molecular weight—
    Donepezil: 379.50 {02}
    Donepezil hydrochloride: 415.96 {01}

Mechanism of action/Effect:

Donepezil is a specific {08} noncompetitive {08} reversible inhibitor of acetylcholinesterase (AChE) {01} {03} {08}, and appears to exert its therapeutic effect by enhancing cholinergic function {01} {03}. By inhibiting the hydrolysis of acetylcholine by AChE, donepezil increases acetylcholine concentrations, thus enhancing cholinergic function {01} {03}. As the dementia progresses, fewer cholinergic neurons are thought to remain functionally intact, and the effects of donepezil may be lessened {01} {03}.

Donepezil exhibits a relatively high degree of selectivity for neuronal AChE {07} {08}; at relevant clinical doses, it has only weak inhibitory effects on butyrylcholinesterase (pseudocholinesterase), an enzyme that is widely distributed in plasma and peripheral tissues {07} {08}. Animal studies have shown that donepezil exhibits tissue selectivity; it significantly inhibits AChE in the brain but causes little inhibition of AChE in smooth, striated, or cardiac muscle {08} {09}.

Donepezil's inhibition of AChE in red blood cells corresponds closely to its effect at synapses in the central nervous system (CNS) {07} {08} {10}. AChE inhibition in red blood cells has been used as an indicator of the clinical effectiveness of donepezil in Alzheimer's disease patients {08}.

Absorption:

Well absorbed, with a relative oral bioavailability of 100% {01} {03} {07}. The rate and extent of absorption are not influenced by food intake or the time of administration {01} {03} {05}.

Distribution:

Steady-state volume of distribution (Vol D) is 12 liters per kg of body weight (L/kg) {01} {14}.

Protein binding:

Very high (approximately 96% {01} {03} {14}, mainly to albumins [about 75%] and alpha 1-acid glycoprotein [about 21%] over the concentration range of 2 to 1000 nanograms per mL) {01} {03}. This binding is not clinically significant at relevant plasma concentrations. {01}

Biotransformation:

Extensive {01} {03}. Donepezil undergoes first pass metabolism {15} to four major metabolites, two of which are known to be active, and a number of minor metabolites {01} {15}. Donepezil is metabolized by cytochrome P450 isoenzymes CYP2D6 and CYP3A4 {01} {03} {15} {21}, and undergoes glucuronidation {01} {03}. The rate of metabolism is slow and does not appear to be saturable {03} {05} {06}. Following administration of radiolabeled donepezil, plasma radioactivity was present primarily as intact donepezil (53%) and as 6- O-desmethyl donepezil (11%) {01} {03}; this metabolite has been reported to inhibit acetylcholinesterase to the same extent as donepezil does in vitro and was found in plasma at concentrations equal to about 20% of donepezil {01} {03}.

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of a single dose of donepezil was decreased by 20% relative to that in 10 healthy age- and sex-matched subjects {01} {21}. With the exception of peak plasma concentrations, there were no statistically significant differences in the pharmacokinetics of donepezil between the groups, and dosage modifications in patients with hepatic function impairment should not be required. {21}

Half-life:


Elimination:

About 70 hours {01} {03} {09} {10} {11} {14}.


Time to peak concentration:

3 to 4 hours {01} {03} {12} {14}.

Time to steady-state concentration

Pharmacokinetics are linear over a dose range of 1 to 10 mg given once a day {01} {03} {12} {13}. Following multiple-dose administration, donepezil accumulates in plasma by fourfold to sevenfold, and steady-state is reached within 15 days {01} {03}. The mean plasma concentration of donepezil at steady-state is 14.2 nanograms per mL. {13}

Elimination:
    Renal, biliary. {23} Following administration of radiolabeled donepezil, total radioactivity recovered over a period of 10 days was approximately 57% in urine (17% as unchanged drug) {01} {03} {15} and 15% in feces {01} {03} {15} (1% as unchanged drug) {15}; 28% remained unrecovered {01} {03}.
    In one study of pairs of age- and sex-matched subjects, the clearance of donepezil in eleven patients with moderate to severe renal function impairment was not found to differ from the clearance in eleven healthy volunteers {22}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other piperidine derivatives may be sensitive to donepezil also {01}. Piperidine derivatives include: rifabutin, methylphenidate, biperiden hydrochloride, trihexyphenidyl hydrochloride, bupivacaine hydrochloride, and paroxetine hydrochloride {03}.

Carcinogenicity

No evidence of a carcinogenic potential was observed in an 88-week study of mice that received approximately 63 times the maximum recommended human dose of donepezil, or in a 104-week study in rats that received approximately 24 times the maximum recommended human dose of donepezil. {23}

Mutagenicity

Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria or in a mouse lymphoma forward mutation assay in vitro {01} {03} {23}. In the chromosome aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were observed {01} {23}. Donepezil was not clastogenic in the in vivo mouse micronucleus test {01} {03} {23} and was not genotoxic in an evaluation of unscheduled DNA synthesis in primary hepatocyte cultures prepared from rats {23}.

Pregnancy/Reproduction
Fertility—
Donepezil demonstrated no effect on fertility in rats given doses approximately eight times the maximum recommended human dose on a mg per square meter of body surface area (mg/m 2) basis {01} {03}.

Pregnancy—
Adequate and well-controlled studies have not been done in humans {01} {03}.

Studies in pregnant rats and rabbits at doses approximately 13 and 16 times, respectively, the maximum recommended human dose on a mg/m 2 basis showed no evidence of teratogenic potential {01} {03}. However, in a study of pregnant rats that received approximately eight times the maximum recommended human dose on a mg/m 2 basis from day 17 of gestation through day 20 postpartum, a slight increase in stillbirths and a slight decrease in pup survival through day 4 postpartum were observed {01} {03}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether donepezil is distributed into breast milk {01} {03}; however, use of donepezil is not recommended during breast-feeding {01} {03}.

Pediatrics

Appropriate studies on the relationship of age to the effects of donepezil have not been performed in the pediatric population. Safety and efficacy have not been established {01} {03}.


Geriatrics


Mean plasma donepezil concentrations measured during therapeutic monitoring of elderly patients with Alzheimer's disease were comparable to those observed in young healthy volunteers {01}. Although the plasma half-life and the time to peak plasma concentration (t max) were longer in the elderly than in young healthy volunteers, the area under the plasma-concentration–time curve (AUC), peak plasma concentration (C max), and oral clearance did not differ between the two groups {06}; differences probably were due to the increased volume of distribution at steady-state {06}. In general, modification of donepezil doses in the elderly is not necessary {06}.

The incidence of nausea, diarrhea, vomiting, insomnia, fatigue, and anorexia increases with increasing age {03}. Caution is advised regarding use of donepezil in low-body-weight elderly patients, especially those ³ 85 years of age, due to the potential for significant weight loss {03}.


Pharmacogenetics

No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of donepezil {01} {03}. However, retrospective pharmacokinetic analysis suggests that gender and race (Japanese and caucasian) do not affect the clearance of donepezil {01} {03}.

Surgical

Because donepezil is a cholinesterase inhibitor, it is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia {01} {03}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: In vitro studies of donepezil and other highly protein-bound medications have shown no displacement of or by digoxin {01} {03} {19}, furosemide {01} {03}, or warfarin {01} {03} {20}. Other in vitro studies indicate little probability that donepezil interferes with the clearance of other drugs metabolized by CYP3A4 isoenzymes (e.g., cisapride, terfenadine) or by CYP2D6 isoenzymes (e.g., imipramine) {01} {03}. It is not known if donepezil has any potential for enzyme induction. {01} {03}
Formal pharmacokinetic studies showed no significant effects of donepezil on the pharmacokinetics of cimetidine {01} {03} {16}, digoxin {01} {03} {19}, theophylline {01} {03} {18}, or warfarin {01} {03} {20}. Similarly, metabolism of donepezil is not significantly affected by concurrent administration of cimetidine {01} {03} {16} or digoxin {01} {03} {19}.
Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Anticholinergics{01}{03}{23} (see Appendix II )     (cholinesterase inhibitors such as donepezil have the potential to interfere with the activity of these medications {01} {03} {23})


Anti-inflammatory drugs, nonsteroidal (NSAIDs){01}{03}    (donepezil may increase gastric acid secretion due to increased cholinergic activity; patients should be monitored for symptoms of active or occult gastrointestinal bleeding {01} {03})


Carbamazepine{01}{03} or
Dexamethasone{01}{03} or
Phenobarbital{01}{03} or
Phenytoin{01}{03} or
Rifampin{01}{03}    (these medications may induce the isoenzymes CYP2D6 and CYP3A4, thus increasing the rate of elimination of donepezil {01})


Cholinergic agonists (e.g., bethanechol){01}{03} or
Neuromuscular blocking agents metabolized by plasma cholinesterase (e.g., succinylcholine, mivacurium){01}{03}    (a synergistic effect may be expected with concurrent use of these medications and donepezil {01})


Ketoconazole{01}{03}{17}{23}    (as an inhibitor of the CYP3A4 isoenzyme, ketoconazole has been shown to inhibit the metabolism of donepezil in vitro ; inhibition of metabolism is unlikely to produce an increase in adverse effects or a change in the effects of donepezil due to the low plasma concentrations of active metabolites and their inability to cross the blood–brain barrier {23})


Quinidine{01}{03}    (as an inhibitor of the CYP2D6 isoenzyme, quinidine has been shown to inhibit the metabolism of donepezil in vitro ; clinical significance is not known {01} {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
Asthma, history of{01}{03} or
Chronic obstructive pulmonary disease{01}{03}    (cholinomimetic actions of cholinesterase inhibitors may aggravate the condition {01} {03})


» Cardiovascular conditions{01}{03} , such as:
Sick sinus syndrome{01}{03}
Supraventricular conduction problems{01}{03}
Unexplained syncopal episodes{03}    (cholinesterase inhibitors such as donepezil may have vagotonic effects on heart rate [e.g., bradycardia]; syncopal episodes have been reported {01} {03})


Hepatic function impairment{01}    (metabolism of donepezil may be impaired)


» Peptic ulcer disease, or history of{01}{03}    (cholinesterase inhibitors may increase gastric acid secretion due to increased cholinergic activity; condition may be exacerbated {01} {03})


Seizures, history of{01}{03}    (cholinomimetics are believed to have the potential to cause generalized seizures; however, seizure activity also may be a manifestation of the Alzheimer's disease state {01} {03})


Sensitivity to donepezil or to other piperidine derivatives{01}
Urinary tract obstruction    (cholinomimetics may cause bladder outflow obstruction {01} {03})




Side/Adverse Effects

Note: Adverse effects are generally mild to moderate, and transient in nature; they may occur most often during dose initiation or escalation. {07} The frequency of common adverse effects may be affected by the rate of dosage titration. {03}
The incidence of nausea, diarrhea, vomiting, insomnia, fatigue, and anorexia increases with increasing dose {23} and with increasing age {03}. Also, adverse effects occur more commonly in patients who are ³ 85 years of age, female, or of low body weight. {03}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Anorexia{01}{03}{11} (loss of appetite)
    
diarrhea{01}{03}{07}{08}{10}{11}{12}{13}
    
fatigue{01}{03}{05}{11}{12} (unusual tiredness or weakness)
    
insomnia{01}{03}{10}{11}{12}{13} (trouble in sleeping)
    
muscle cramps{01}{03}{11}
    
nausea{01}{03}{05}{07}{08}{09}{10}{11}{12}{13}
    
vomiting{01}{03}{07}{08}{09}{11}{12}

Incidence less frequent
    
Abnormal dreams{01}{03}
    
arthritis{01}{03} (joint pain, stiffness, or swelling)
    
constipation{07}{08}
    
dizziness{01}{03}{05}{08}{09}{10}{11}{13}
    
ecchymosis{01}{03} (unusual bleeding or bruising)
    
frequent urination{01}{03}
    
headache{01}{03}{05}{08}{10}{11}{13}
    
mental depression{01}{03}{10}
    
pain{01}{03}{08}{10}{11}
    
somnolence{01}{03} (drowsiness)
    
syncope{01}{03}{09} (fainting)
    
weight loss{01}{03}{11}

Incidence rare
    
Aphasia{01}{03} (problems with speech)
    
ataxia{01}{03}{09} (clumsiness or unsteadiness)
    
atrial fibrillation{01}{03} (irregular heartbeat; dizziness; fainting)
    
bloating{01}{03}
    
blurred vision{01}{03}
    
bronchitis{01}{03}{09} (cough; shortness of breath; tightness in chest; wheezing)
    
cataract{01}{03}
    
chest or epigastric pain{01}{03}{09} (pain in chest, upper stomach, or throat)
    
dehydration{01}{03}{09} (confusion; decrease in urination; dizziness; dryness of mouth; increase in heart rate and breathing; low blood pressure; severe thirst; sunken eyes; unusual tiredness or weakness; wrinkled skin)
    
diaphoresis{01}{03} (increased sweating)
    
dyspnea{01}{03} (troubled breathing)
    
eye irritation{01}{03}{22}
    
fecal incontinence{01}{03} (loss of bowel control)
    
gastrointestinal bleeding{01}{03} (black, tarry stools)
    
hot flashes{01}{03}
    
hypertension or hypotension{01}{03}{09} (high or low blood pressure)
    
increased libido{01}{03} (increase in sexual desire or performance)
    
mood or mental changes, including abnormal crying{01}{03} , aggression{01}{03} , agitation{09}{10}{11} , delusions{01}{03} , irritability{01}{03} , nervousness{01}{03} , or restlessness{01}{03}
    
nocturia{01}{03} (increased urge to urinate during the night)
    
paresthesia{01}{03} (burning, prickling, or tingling sensations)
    
pharyngitis{01}{03} (sore throat)
    
pruritus{01}{03} (itching)
    
tremor{01}{03}
    
upper respiratory infection{10}{11} (chills; cough; fever; nasal congestion; runny nose; sneezing; sore throat)
    
urinary incontinence{01}{03} (loss of bladder control)
    
urinary tract infection{09}{10} (bloody or cloudy urine; difficult or painful urination; frequent urge to urinate)
    
urticaria{01}{03} (hives)
    
vasodilation{01}{03}{08} (flushing of skin)
    
vertigo{01}{03}





Overdose
For specific information on the agents used in the management of donepezil overdose, see Atropine in the Anticholinergics/Antispasmodics (Systemic) monograph.

For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Overdosage with cholinesterase inhibitors may result in cholinergic crisis characterized by:
    
Bradycardia{01}{03} (slow heartbeat)
    
hypotension{01}{03} (low blood pressure)
    
muscle weakness, increasing{01}{03} —may result in death if respiratory muscles are involved{01}{03}
    
nausea, severe{01}{03}
    
respiratory depression{01}{03} (troubled breathing)
    
salivation, increased{01}{03} (increased watering of mouth)
    
seizures{01}{03}
    
sweating, increased{01}{03}
    
vomiting, severe{01}{03}


Treatment of overdose
To enhance elimination—It is not known whether donepezil and/or its metabolites can be removed by hemodialysis, peritoneal dialysis, or hemofiltration {01} {03}.

Specific treatment—Tertiary anticholinergics such as atropine may be used as antidotes {01} {03}. Intravenous atropine sulfate titrated to effect is recommended; initially, an intravenous dose of 1 to 2 mg is given, with subsequent doses based upon clinical response {01} {03}. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when coadministered with quaternary anticholinergics such as glycopyrrolate {01} {03}.

Supportive care—General supportive measures should be utilized. {01} Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient [Donepezil (Systemic)] .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to donepezil or other piperidine derivatives





Breast-feeding—Not recommended
Other medical problems, especially cardiovascular conditions and peptic ulcer disease



Surgical
A synergistic effect occurs when donepezil is used concurrently with neuromuscular blocking agents metabolized by plasma cholinesterase (e.g., succinylcholine)

Proper use of this medication
» Taking medication exactly as directed; not taking more medication than the amount prescribed because of increased risk of adverse effects

Taking donepezil at bedtime

» Proper dosing
Missed dose: Skipping the missed dose and returning to regular dosing schedule; not doubling doses

» Proper storage

Precautions while using this medication
» Importance of keeping regular appointments with physician

» Caution if any kind of surgery or emergency treatment is required; informing physician or dentist in charge that donepezil is being taken

» Caution if dizziness, drowsiness, or clumsiness or unsteadiness occurs

» Suspected overdose—Getting emergency help at once


Side/adverse effects
Signs of potential side effects, especially anorexia, diarrhea, fatigue, insomnia, muscle cramps, nausea, vomiting, abnormal dreams, arthritis, constipation, dizziness, ecchymosis, frequent urination, headache, mental depression, pain, somnolence, syncope, weight loss, aphasia, ataxia, atrial fibrillation, bloating, blurred vision, bronchitis, cataract, chest or epigastric pain, dehydration, diaphoresis, dyspnea, eye irritation, fecal incontinence, gastrointestinal bleeding, hot flashes, hypertension or hypotension, increased libido, mood or mental changes, nocturia, paresthesia, pruritus, tremor, upper respiratory infection, urinary incontinence, urinary tract infection, urticaria, vasodilation, and vertigo


General Dosing Information
Donepezil should be taken in the evening, just prior to retiring {01} {03}. However, if insomnia is a problem, this medication may be taken during the day. {23} Donepezil may be taken with or without food {01} {03}.

In a population of cognitively-impaired persons such as Alzheimer's disease patients, safe use of donepezil (and all other medications) may require supervision. {03}


Oral Dosage Forms

DONEPEZIL HYDROCHLORIDE TABLETS

Usual adult dose
Alzheimer's dementia
Oral, initially 5 mg once a day, taken in the evening just prior to retiring {01} {03}. Although a higher dose of 10 mg did not provide a statistically significant greater clinical benefit than the 5-mg dose, a daily dose of 10 mg may provide additional benefit for some patients {01}. However, the 10-mg dose is likely to be associated with a higher incidence of cholinergic side effects than the 5-mg dose {01}. If a trial of the 10-mg dose is desired, dosage should not be increased until patients have been on a daily dose of 5 mg for four to six weeks because steady-state is not achieved for fifteen days and because the rate of adverse effects may be influenced by the rate of dose escalation {01} {03}.


Usual adult dosing limits
10 mg a day. {03}

Usual pediatric dose
Safety and efficacy have not been established {01}.

Usual geriatric dose
See Usual adult dose .

Note: In elderly women of low body weight, the dose should not exceed 5 mg a day. {03}


Strength(s) usually available
U.S.—


5 mg (Rx) [Aricept (film-coated) (lactose monohydrate)]


10 mg (Rx) [Aricept (film-coated) (lactose monohydrate)]

Canada—


5 mg (Rx) [Aricept (film-coated) (lactose monohydrate)]


10 mg (Rx) [Aricept (film-coated) (lactose monohydrate)]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF). {01} {03}

Auxiliary labeling:
   • May cause dizziness.
   • May cause drowsiness.



Developed: 06/11/1999



References
  1. Aricept package insert (Eisai—US), Rev 4/98, Rec 4/1/99.
  1. Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 252.
  1. Aricept product monograph (Eisai—Canada), Rev 8/8/97, Rec 10/29/97.
  1. Donepezil (Aricept) for Alzheimer's disease. Med Lett Drugs Ther 1997 Jun 6; 39(1002): 53-4.
  1. Mihara M, Ohnishi A, Hasegawa J, et al. Pharmacokinetics of E2020, a new compound for Alzheimer's disease, in healthy male volunteers. Int J Clin Pharmacol Ther Toxicol 1993; 31(5): 223-9.
  1. Ohnishi A, Mihara M, Kamakura H, et al. Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer's disease, in healthy young and elderly subjects. J Clin Pharmacol 1993; 33: 1086-91.
  1. Dickinson BD, editor. UHC drug monograph: Donepezil. UHC (University HealthSystem Consortium) Services Corporation; 1996. p. 1-14.
  1. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Donepezil Study Group. Dementia 1996; 7: 293-303.
  1. Rogers SL, Farlow MR, Doody RS, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology 1998 Jan; 50: 136-45.
  1. Rogers SL, Friedhoff LT. Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: an interim analysis of the results of a US multicentre open label extension study. Eur Neuropsychopharmacol 1998; 8(1): 67-75.
  1. Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease. Donepezil Study Group. Arch Intern Med 1998 May 11; 158: 1021-31.
  1. Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses. Br J Clin Pharmacol 1998; 46 Suppl 1: 1-6.
  1. Rogers SL, Cooper NM, Sukovaty R, et al. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses. Br J Clin Pharmacol 1998; 46 Suppl 1: 7-12.
  1. Tiseo PJ, Rogers SL, Freidhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol 1998; 46 Suppl 1: 13-8.
  1. Tiseo PJ, Perdomo CA, Friedhoff LT. Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study. Br J Clin Pharmacol 1998; 46 Suppl 1: 19-24.
  1. Tiseo PJ, Perdomo CA, Freidhoff LT. Concurrent administration of donepezil HCl and cimetidine: assessment of pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol 1998; 46 Suppl 1: 25-9.
  1. Tiseo PJ, Perdomo CA, Freidhoff LT. Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses. Br J Clin Pharmacol 1998; 46 Suppl 1: 30-4.
  1. Tiseo PJ, Foley K, Freidhoff LT. Concurrent administration of donepezil HCl and theophylline: assessment of pharmacokinetic changes following multiple-dose administration in healthy volunteers. Br J Clin Pharmacol 1998; 46 Suppl 1: 35-9.
  1. Tiseo PJ, Perdomo CA, Freidhoff LT. Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes. Br J Clin Pharmacol 1998; 46 Suppl 1: 40-4.
  1. Tiseo PJ, Foley K, Friedhoff LT. The effect of multiple doses of donepezil HCl on the pharmacokinetic and pharmacodynamic profile of warfarin. Br J Clin Pharmacol 1998; 46 Suppl 1: 45-50.
  1. Tiseo PJ, Vargas R, Perdomo CA, et al. An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function. Br J Clin Pharmacol 1998; 46 Suppl 1: 51-5.
  1. Tiseo PJ, Foley K, Friedhoff LT. An evaluation of the pharmacokinetics of donepezil HCl in patients with moderately to severely impaired renal function. Br J Clin Pharmacol 1998; 46 Suppl 1: 56-60.
  1. Manufacturer comment, 6/6/99.
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