Donepezil

Pronunciation: doe-NEP-e-zil
Class: Cholinesterase inhibitor

Trade Names

Aricept
- Tablets 5 mg
- Tablets 10 mg
- Tablets 23 mg
- Tablets, orally disintegrating 5 mg
- Tablets, orally disintegrating 10 mg

Pharmacology

Increases acetylcholine by inhibiting acetylcholinesterase, thereby increasing cholinergic function.

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Pharmacokinetics

Absorption

T _max for the 10 and 23 mg tablets is approximately 3 and 8 h, respectively. C _max is almost 2–fold higher for the 23 mg tablet compared with the 10 mg tablet. Steady state is reached in 15 days.

Distribution

Vd is 12 to 16 L/kg (at steady state). Approximately 96% protein bound (75% to albumin and 21% alpha-1 acid glycoprotein)

Metabolism

Metabolized by CYP2D6 and CYP3A4, and undergoes glucuronidation to 4 major metabolites (2 active) and several minor metabolites.

Elimination

The elimination half-life is approximately 70 h. Cl is 0.13 to 0.19 L/h/kg. Approximately 57% recovered in urine and 15% in feces; approximately 17% of dose is recovered unchanged in urine.

Special Populations

Cl did not differ in patients with moderate to severe renal impairment.

Cl decreased 20% in patients with stable alcoholic cirrhosis.

When compared with patients 65 y of age, patients 90 y of age have a 17% decrease in Cl, while patients 40 y of age have a 33% increase in Cl. This effect may not be clinically significant.

Cl was not affected to any important degree.

Cl was not affected to any important degree by race (Japanese and white patients).

For body weight from 50 to 110 kg, Cl increased from 7.77 to 14.04 L/h, with a value of 10 L/h for 70 kg individuals.

Indications and Usage

Treatment of mild to severe dementia of the Alzheimer type.

Unlabeled Uses

Autism, traumatic brain injury, vascular dementia, poststroke aphasia, improvement in memory in multiple sclerosis patients.

Contraindications

Hypersensitivity to donepezil or piperidine derivatives.

Dosage and Administration

PO 5 mg once daily; may increase to 10 mg once daily after 4 to 6 wk.

PO Start with 5 mg once daily. Increase to 10 mg once daily after 4 to 6 wk. A dosage of 23 mg once daily may be given after the patient has been on 10 mg once daily for at least 3 months.

General Advice

• Orally disintegrating tablets are bioequivalent to tablets.
• Administer in the evening, just prior to bedtime.
• May be taken without respect to food.
• Allow the oral disintegrating tablet to dissolve on the tongue and follow with water.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Possible reduction of anticholinergic effects. Monitor the clinical response and adjust treatment dose as needed.

Donepezil increases gastric acid secretions caused by increased cholinergic activity. The risk of stomach ulcers may be increased. Therefore, monitor for active or occult GI bleeding.

Synergistic effects may occur. Monitor the clinical response and adjust treatment dose as needed.

May increase donepezil rate of elimination, decreasing donepezil plasma concentrations. Monitor the clinical response and adjust the donepezil dose as needed.

May inhibit donepezil metabolism, increasing donepezil plasma concentrations. Monitor the clinical response and adjust the donepezil dose as needed.

Adverse Reactions

Cardiovascular

Hypertension (3%); hemorrhage, syncope (2%); abnormal ECG, atrial fibrillation, bradycardia, heart failure, hot flashes, hypotension, vasodilation (at least 1%); heart block (postmarketing).

CNS

Insomnia (14%); headache (10%); dizziness, fatigue (8%); abnormal dreams, depression, hallucinations, hostility, nervousness (3%); asthenia, confusion, emotional lability, personality disorder, somnolence (2%); abnormal crying, abnormal gait, aggression, agitation, anxiety, aphasia, ataxia, convulsions, delusions, increased libido, irritability, paresthesia, restlessness, tremor, vertigo, wandering (at least 1%); NMS (postmarketing).

Dermatologic

Eczema (3%); diaphoresis, pruritus, rash, skin ulcer, urticaria (at least 1%).

EENT

Blurred vision, cataract, eye irritation, pharyngitis, sore throat (at least 1%).

GI

Nausea (19%); diarrhea (15%); vomiting (9%); anorexia (8%); abdominal pain, bloating, constipation, dyspepsia, fecal incontinence, gastroenteritis, GI bleeding, epigastric pain (at least 1%); pancreatitis (postmarketing).

Genitourinary

Urinary incontinence (3%); frequent urination (2%); cystitis, glucosuria, hematuria, nocturia, UTI (at least 1%).

Hepatic

Increased ALT/AST (at least 1%); cholecystitis, hepatitis (postmarketing).

Hematologic-Lymphatic

Ecchymosis (5%); anemia (at least 1%); hemolytic anemia (postmarketing).

Metabolic-Nutritional

Weight decrease (5%); increased CPK (3%); dehydration, hyperlipemia (2%); edema, increased alkaline phosphatase and LDH, peripheral edema (at least 1%); hyponatremia (postmarketing).

Musculoskeletal

Muscle cramps (8%); back pain (3%); arthritis (2%); bone fracture (at least 1%).

Respiratory

Bronchitis, dyspnea, increased cough, pneumonia (at least 1%).

Miscellaneous

Accident (13%); infection (11%); pain (various locations) (9%); chest pain, contusion, fever (2%); flu syndrome, fungal infection, toothache (at least 1%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined. The molecular weight (approximately 416) and long plasma elimination half-life (approximately 70 h) suggest donepezil will be excreted into breast milk. The extensive protein binding (approximately 0.96%) should limit this excretion.

Children

Safety and efficacy not established.

CV effects

May have vagotonic effects on the sinoatrial and AV nodes.

Concomitant medical conditions

Increases cholinergic activity and, therefore, can affect other organ systems, possibly leading to bradycardia or heart block, bladder outflow obstruction, increased gastric acid secretion, generalized convulsions, or bronchoconstriction. Use with caution in patients susceptible to these reactions.

GI effects

Diarrhea, nausea, and vomiting appear more frequently with higher doses and may last for 1 to 3 weeks. Because of increased cholinergic activity increasing gastric secretion, patients are at an increased risk of developing occult GI bleeding, especially those at increased risk for developing ulcers (eg, history of ulcer disease or those receiving concurrent NSAIDs).

Lower-weight patients

Patients weighing less than 55 kg reported more nausea and vomiting and decreased weight compared with patients weighing 55 kg or more.

Overdosage

Symptoms

Cholinergic crisis (eg, bradycardia, collapse, convulsions, hypotension, muscle weakness, respiratory depression, salivation, severe nausea, sweating, vomiting).

Patient Information

• Advise patient or caregiver that this drug does not alter the Alzheimer process and that the effectiveness of the medication may lessen in time.
• Advise patient to take prescribed dose once daily in the evening just before bedtime.
• Advise patient that donepezil can be taken without regard to meals but to take with food if stomach upset occurs.
• Advise patient receiving orally disintegrating tablet to allow tablet to dissolve on tongue and then follow with water.
• Advise patient that if a dose is missed to skip that dose and take next dose at regularly scheduled time. Caution patient not to double the dose to catch up.
• Advise patient or caregiver not to discontinue drug or change dose unless advised by health care provider.
• Caution patient or caregiver not to increase the dose of donepezil if Alzheimer symptoms worsen or do not appear to be improving, but to notify health care provider.
• Advise patient or caregiver that diarrhea, nausea, and vomiting commonly occur, especially during the early phase of treatment with donepezil, but that these symptoms will usually go away within 1 to 3 wk with continued therapy.
• Advise patient to notify health care provider if any of the following occur: appetite loss; depression; fainting; persistent nausea, diarrhea, or vomiting; sleeplessness; any other unexplained change or symptoms.
• Caution patient that donepezil may cause drowsiness or dizziness, and to use caution while driving or performing other activities requiring mental alertness or coordination until tolerance is determined.

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