DEMENTILE

In 2016, the global burden of dementia was estimated to be 43.8 million, demonstrating a significant increase from a global prevalence of 20.2 million in 1990.

Donepezil, also known as Aricept, is a piperidine derivative acetylcholinesterase inhibitor used in the management of the dementia of Alzheimer's Disease, and in some cases, is used to manage other types of dementia.

Donepezil was first approved by the

FDA in 1996, and its extended-release form was approved in combination with Memantine in to manage moderate and severe forms of Alzheimer's dementia. 19, 22 A donepezil transdermal delivery system, Adlarity, was approved by the FDA in March for the treatment of Alzheimer's dementia.

Though it does not alter the progression of Alzheimer's disease, donepezil is effective in managing the symptoms of its associated dementia.

Donepezil, administered Oral 19 or via transdermal delivery system, 24 is indicated for the treatment of dementia of the Alzheimer's type.

It is also available as an extended-release capsule in combination with memantine for the treatment of moderate-to-severe dementia of the Alzheimer's type in patients previously stabilized on 10 mg of donepezil hydrochloride once daily.

Off-label uses include the management of vascular dementia, Parkinson's Disease-associated dementia, and Lewy body dementia, amongst others. 8,

By inhibiting the acetylcholinesterase enzyme, donepezil improves the cognitive and behavioral signs and symptoms of Alzheimer's Disease, which may include apathy, aggression, confusion, and psychosis. 8, 15.

Donepezil is slowly absorbed via the gastrointestinal tract after oral administration.

Tmax is 3-4 hours with a bioavailability of 100% and steady-state concentrations are attained within 15-21 days of administration.

The Tmax in one pharmacokinetic study determined a Tmax of 4.1 ± 1.5 hours.

Cmax of 5 mg donepezil tablets is estimated to be 8.34 ng/mL, according to the Canadian monograph.

AUC of 5 mg donepezil tablets has been determined to be 221.90-225.36 ng.hr/mL.

The volume of distribution of donepezil is 11.8 ± 1.7 L/kg for a 5-mg dose and 11.6 ± 1.91 L/kg for a 10-mg dose.

It is largely distributed in the extravascular compartments.

Donepezil crosses the blood-brain barrier and cerebrospinal fluid concentrations at the above doses have been measured at 15.7%.

The volume of distribution at steady-state according to the FDA label for donepezil ranges from 12-16 L/kg.

Donepezil is metabolized by first pass metabolism in the liver, primarily by CYP3A4, in addition to CYP2D6.

After this, O-dealkylation, hydroxylation, N-oxidation, hydrolysis, and O-glucuronidation occur, producing various metabolites with similar half-lives to the unchanged parent drug.

A study of the pharmacokinetics of radiolabeled donepezil demonstrated that about 53% of plasma radioactivity appeared as donepezil in the unchanged form, and 11% was identified as the metabolite 6-O-desmethyl donepezil, which exerts similar potency inhibition of the acetylcholinesterase enzyme. 8, 19 This drug is heavily metabolized to four primary metabolites, two of which are considered pharmacologically active, as well as to multiple inactive and unidentified metabolites.

Hover over products below to view reaction partners Donepezil 6-O-desmethyl donepezil M1 metabolite, Donepezil M11, Donepezil M2, Donepezil M12, Donepezil M4, Donepezil M6, Donepezil.

In a study of radiolabeled administration donepezil in healthy adults, 57% of measured radioactivity was identified in the urine, and 5% was identified in the feces.

The average elimination half-life of donepezil is about 70 hours according to the results of various studies and the FDA label for donepezil. 8, 19.

One pharmacokinetic study determined the average terminal half-life to be 81.5±22.0 h 6.

According to the

FDA label, the average apparent plasma clearance of this drug is 0.13 – 0.19 L/hr/kg.

A 5 mg dose of donepezil in healthy patients was shown to have a plasma clearance of 0.110±0.02 L/h/kg.

In 10 patients diagnosed with alcoholic cirrhosis, showed a mean decrease in clearance by 20% when compared to the clearance in 10 healthy subjects.

In 4 patients with severe renal impairment compared to 4 healthy subjects, no significant change in clearance was noted.

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LD50 The rat oral LD50 of donepezil is 32.6 mg/kg.

Overdose information

Signs and symptoms of overdose with cholinesterase inhibitors such as donepezil can include severe nausea and vomiting, bradycardia, hypotension, perspiration, seizures, muscle weakness respiratory depression, and collapse.

Significant muscle weakness may result in death if the respiratory muscles are affected by donepezil overdose.

To manage an overdose, anticholinergics can be employed as antidotes.

Atropine at intravenous doses of 1.0-2.0 mg can be administered and titrated according to the clinical response.

Consult the local poison control center for the most updated guidelines on the management of a donepezil overdose.

Whether donepezil can be removed from the body with dialysis is unknown at this time.

Known hypersensitivity to donepezil hydrochloride or to piperidine derivatives Donepezil hydrochloride is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives.

Alzheimer's Disease: 5 mg to 10 mg once daily Moderate to Severe Alzheimer's Disease: 10 mg to 23 mg once daily 2.1 Dosing in Mild to Moderate Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride tablet is 5 mg administered once per day in the evening, just prior to retiring.

The maximum recommended dosage of donepezil hydrochloride tablets in patients with mild to moderate Alzheimer's disease is 10 mg per day. A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for to 6 weeks. 2.2 Dosing in Moderate to Severe Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride tablet is 5 mg administered once per day in the evening, just prior to retiring.

The maximum recommended dosage of donepezil hydrochloride tablets in patients with moderate to severe Alzheimer's disease is 23 mg per day. A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for to 6 weeks.

A dose of 23 mg per day should not be administered until patients have been on a daily dose of 10 mg for at least 3 months. 2.3 Administration Information Donepezil hydrochloride tablets should be taken in the evening, just prior to retiring.

Donepezil hydrochloride tablets can be taken with or without food.

The donepezil hydrochloride 23 mg tablet should not be split, crushed, or chewed.

Donepezil Hydrochloride Tablets USP Donepezil Hydrochloride Tablets USP, 23 mg are reddish brown, round, film coated tablets, containing 23 mg of donepezil hydrochloride, debossed with 'G52' on one side and 'LU' on the other side, which are supplied as follows: NDC 68180-527-06 Bottle of 30s NDC 68180-527-09 Bottle of 90s Storage: Store at 25°C (77°F); excursions permitted to to 30°C (59 to 86°F) .

Protect from moisture.

There are no adequate data on the developmental risks associated with the use of donepezil hydrochloride in pregnant women.

In animal studies, developmental toxicity was not observed when donepezil was administered to pregnant rats and rabbits during organogenesis, but administration to rats during the latter part of pregnancy and throughout lactation resulted in increased stillbirths and decreased offspring survival at clinically relevant doses.

In the

U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.

The background risks of major birth defects and miscarriage for the indicated population are unknown.

Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 6 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m 2 basis) and 10 mg/kg/day (approximately 7 times the MRHD on a mg/m 2 basis), respectively.

Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day at the highest dose.

The no-effect dose of 3 mg/kg/day is approximately equal to the MRHD on a mg/m 2 basis.

There are no data on the presence of donepezil or its metabolites in human milk, the effects on the breastfed infant, or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for donepezil hydrochloride and any potential adverse effects on the breastfed infant from donepezil hydrochloride or from the underlying maternal condition.

The safety and effectiveness in pediatric patients have not been established.

Alzheimer's disease is a disorder occurring primarily in individuals over 55 years of age.

The mean age of patients enrolled in the clinical studies with donepezil hydrochloride was 73 years; 80% of these patients were between and 84 years old, and 49% of patients were at or above the age of 75.

The efficacy and safety data presented in the clinical trials section were obtained from these patients.

There were no clinically significant differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old.