Donepezil Hydrochloride

Approved Indications:

• Alzheimer’s disease: Treatment of mild, moderate, and severe dementia of the Alzheimer’s type.
• Cognitive impairment associated with Alzheimer’s: To improve cognition, memory, and function in Alzheimer’s patients.

Off-label / Clinically Accepted Uses:

• Dementia associated with Parkinson’s disease (off-label)
• Other neurodegenerative cognitive disorders (less common, limited evidence)

Route: Oral

Adults (Alzheimer’s Disease):

• Initial dose: 5 mg once daily at bedtime
• Maintenance dose: After 4–6 weeks, increase to 10 mg once daily as tolerated
• Maximum dose: 10 mg daily; in some regions, extended-release formulations allow up to 23 mg daily for moderate to severe cases.

Elderly:

• Same as adults; monitor closely for adverse effects

Pediatrics:

• Not recommended or approved

Renal/Hepatic Impairment:

• No dosage adjustment for mild to moderate impairment
• Severe hepatic impairment: Use with caution; insufficient data for dose recommendation

Administration Notes:

• Can be taken with or without food
• Administer at the same time each day, preferably bedtime

Donepezil is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for breaking down acetylcholine in the synaptic cleft. By inhibiting this enzyme, donepezil increases acetylcholine concentrations in the brain, enhancing cholinergic neurotransmission in the central nervous system. This action helps improve cognitive function and memory in Alzheimer’s disease, where cholinergic neurons are progressively lost.

• Absorption: Rapid and complete oral absorption; bioavailability ~100%
• Distribution: Crosses the blood-brain barrier; volume of distribution approximately 12 L/kg
• Metabolism: Extensively metabolized in the liver by CYP2D6 and CYP3A4 enzymes
• Half-life: Approximately 70 hours, allowing once-daily dosing
• Elimination: Metabolites and unchanged drug excreted mainly via urine

• Pregnancy: FDA Category C
• Animal studies show adverse effects at high doses; human data lacking
• Use only if potential benefit justifies the potential risk
• Lactation:
• Unknown if excreted in human milk
• Caution advised; weigh benefits against potential risks to the infant

• Primary Class: Cholinesterase inhibitor
• Subclass: Central nervous system agent for dementia

• Known hypersensitivity to donepezil or any excipients
• History of hypersensitivity reactions to piperidine derivatives
• Severe hepatic impairment (relative contraindication)

• Use cautiously in patients with:
• Cardiac conduction abnormalities (e.g., sick sinus syndrome, bradycardia)
• Asthma or chronic obstructive pulmonary disease (COPD)
• Seizure disorders
• Gastrointestinal bleeding or ulcers due to increased cholinergic activity
• Monitor for cholinergic side effects and signs of overdose
• May increase gastric acid secretion; caution with NSAIDs due to GI risk

Common:

• Gastrointestinal: Nausea, diarrhea, vomiting, anorexia
• Central nervous system: Insomnia, dizziness, headache
• Muscle cramps
• Fatigue

Less Common:

• Bradycardia
• Syncope
• Weight loss
• Urinary incontinence

Rare / Serious:

• Seizures
• Gastrointestinal bleeding
• Heart block or arrhythmias
• Stevens-Johnson syndrome (very rare hypersensitivity)

Side effects typically appear early and may diminish with continued treatment.

• CYP2D6 and CYP3A4 inhibitors (e.g., ketoconazole, quinidine): May increase donepezil levels, increasing risk of adverse effects.
• CYP inducers (e.g., rifampin, carbamazepine): May reduce donepezil efficacy.
• Anticholinergics: May antagonize donepezil’s effects.
• Cholinergic agents: Additive cholinergic side effects.
• NSAIDs: Increased risk of gastrointestinal bleeding.

• Extended-release formulations (up to 23 mg daily) approved for moderate to severe Alzheimer’s with evidence of modest additional benefit.
• Recent dementia management guidelines recommend cholinesterase inhibitors like donepezil as part of standard care.
• Ongoing research into combination therapies and earlier use in mild cognitive impairment stages.

• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and light
• Keep tablets in original packaging until use
• Keep out of reach of children