donepezil hydrochloride
Aricept

Available forms
Available by prescription only
Tablets: 5 mg, 10 mg

Indications and dosages
 Mild to moderate dementia of the Alzheimer’s type. Adults: Initially, 5 mg P.O. daily h.s. After 4 to 6 weeks, dosage may be increased to 10 mg daily.

Pharmacodynamics
Anticholinesterase action: Drug is believed to inhibit the enzyme acetylcholinesterase in the CNS, increasing the concentration of acetylcholine and temporarily improving cognitive function in patients with Alzheimer’s disease. Drug doesn’t alter the course of the underlying disease process.

Pharmacokinetics
Absorption: Well absorbed with a relative bioavailability of 100%. Steady state is reached within 15 days.
Distribution: Steady-state volume of distribution is 12 L/kg. Donepezil is about 96% bound to plasma proteins, mainly to albumins (about 75%) and a1-acid glycoprotein (about 21%) over the concentration range of 2 to 1,000 ng/ml.
Metabolism: Extensively metabolized to four major metabolites (two are known to be active) and several minor metabolites (not all have been identified). Donepezil is metabolized by CYP-450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.
Excretion: Both excreted in the urine intact and extensively metabolized by the liver. Elimination half-life is about 70 hours and mean apparent plasma clearance is 0.13 L/hour/kg. About 17% of drug is eliminated by the kidneys as unchanged drug.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or piperidine derivatives. Use very cautiously in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions because drug may cause bradycardia. Use cautiously in patients with CV disease, asthma, or history of ulcer disease and in those taking NSAIDs.

Interactions
Drug-drug. Anticholinergics: May interfere with anticholinergic activity. Monitor patient.
Bethanechol, succinylcholine: May produce additive effects. Monitor patient closely.
Carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin: May speed donepezil elimination. Monitor patient.
Cholinomimetics, cholinesterase inhibitors: May produce synergistic effect. Monitor patient closely.
NSAIDs: May increase gastric acid secretion because of donepezil’s cholinergic activity. Monitor patient for active or occult GI bleeding.
Drug-herb. Jaborandi, pill-bearing spurge: May cause additive effect; may increase risk of toxicity. Tell patient to use together cautiously.

Adverse reactions
CNS: abnormal dreams or crying, aggression, aphasia, ataxia, dizziness, syncope, fatigue, depression, headache, insomnia, irritability, nervousness, paresthesia, restlessness, somnolence, seizures, tremor, vertigo, pain.
CV: atrial fibrillation, chest pain, hypertension, vasodilation, hypotension.
EENT: blurred vision, cataract, eye irritation, sore throat, toothache.
GI: anorexia, bloating, diarrhea, epigastric pain, fecal incontinence, GI bleeding, nausea, vomiting.
GU: frequent urination, nocturia.
Metabolic: dehydration, weight loss.
Musculoskeletal: arthritis, bone fracture, muscle cramps.
Respiratory: bronchitis, dyspnea.
Skin: diaphoresis, pruritus, urticaria, ecchymoses.
Other: flulike symptoms, increased libido, hot flashes.

Effects on lab test results
None reported.

Overdose and treatment
Overdose can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and seizures. Increasing muscle weakness may also occur and may result in death if respiratory muscles are involved.
 Tertiary anticholinergics such as atropine may be used as an antidote for drug overdose. I.V. atropine sulfate titrated to effect is recommended; give an initial dose of 1 to 2 mg I.V. and base subsequent doses on response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when administered with quaternary anticholinergics such as glycopyrrolate. It isn’t known whether donepezil or its metabolites can be removed by dialysis.

Special considerations
• Diarrhea, nausea, and vomiting occur more frequently with the 10-mg dose than with the 5-mg dose. These effects are mostly mild and transient, sometimes lasting 1 to 3 weeks, and resolve during continued drug therapy.
• Although not observed in clinical trials, drug may cause bladder outflow obstruction.
• Cholinomimetics have potential to cause generalized seizures. However, seizure activity also may be caused by Alzheimer’s disease.
• Drug may increase gastric acid secretion. Closely monitor patients at increased risk for development of ulcers for symptoms of active or occult GI bleeding.
Breast-feeding patients
• It isn’t known whether donepezil appears in breast milk. Avoid use in breast-feeding women.
Pediatric patients
• Safety and efficacy in children haven’t been established.
Geriatric patients
• Mean plasma drug levels of elderly patients with Alzheimer’s disease are comparable with those observed in young healthy volunteers.

Patient education
• Explain to patient and caregiver that drug doesn’t alter disease but can stabilize or alleviate symptoms.
• Advise caregiver that effects of therapy depend on drug administration at regular intervals.
• Tell caregiver to give drug in the evening, just before bedtime.
• Advise patient and caregiver to immediately report significant adverse effects or changes in overall health status.
• Tell patient to inform medical personnel that he’s using this drug before he receives anesthesia.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use