The chemical name of donepezil is (±)-2,3-bishydroxy-5,6-bimethoxy-2-{[1-(phenylmethyl)-4-quanidinyl]methyl}-1H-inden-1-one hydrochloride. The molecular formula is C24H29NO3Cl. Molecular weight is 415.96. The inactive ingredients of this drug are lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate.
Pharmacological effects
Pharmacodynamics Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, an enzyme found mainly in the brain. Donepezil hydrochloride inhibited acetylcholinesterase 1252-fold more strongly than butyrylcholinesterase, which is found mainly outside the central nervous system, in in vitro experiments. In clinical trials, patients with Alzheimer’s type dementia who received 5 mg or 10 mg of this drug orally once a day had 63.6% and 77.3% inhibition of acetylcholinesterase activity (erythrocyte membrane), respectively, at steady state.
The inhibition of erythrocyte acetylcholinesterase activity (AChE) by donepezil hydrochloride was associated with changes in the ADAS-cog scale, a sensitive scale that examines certain aspects of cognitive function. The potential of donepezil hydrochloride to alter the primary neuropathological processes of the disease has not been studied.
Preclinical safety information : Extensive animal testing has shown that the drug has few effects other than a pharmacological effect of cholinergic neuroexcitation. No teratogenic effects of donepezil hydrochloride were observed in bacterial Ames revertant mutation assays or in mouse in vitro lymphoma forward mutation assays. Some teratogenic effects were observed in in vitro experiments, but only at concentrations that were significantly toxic to cells and at concentrations greater than 3000 times the steady-state concentration in patients in clinical trials. In an in vivo micronucleus model in mice, donepezil hydrochloride had no teratogenic effect. In long-term carcinogenicity studies in rats and rabbits, there was no evidence of carcinogenic potential. Donepezil hydrochloride had no effect on reproductive function in rats and was not teratogenic in rats and rabbits, but had a slight effect on the early survival of stillbirths and litters when given to pregnant rats at 50 times the human dose.
Pharmacokinetics
Pharmacokinetics Absorption: Peak plasma concentration is reached 3-4 hours after oral administration. The elimination half-life is approximately 70 hours, so steady-state will be reached slowly with multiple daily single-dose administrations. Steady state is reached within 3 weeks of treatment initiation, after which plasma donepezil hydrochloride concentrations and corresponding pharmacodynamic activity vary minimally throughout the day. Diet has no effect on the absorption of donepezil hydrochloride.
Distribution : Approximately 95% of donepezil hydrochloride is bound to human plasma proteins. The plasma protein binding of the active metabolite, 6-O-desmethyl donepezil, is unknown. The distribution of donepezil hydrochloride in different tissues has not been clearly studied. However, in a radiological mass balance study done in healthy adult male volunteers, 28% of the marker remained unrecovered 240 hours after administration of a single dose of 14C-labeled donepezil hydrochloride, indicating that donepezil hydrochloride and/or its metabolites were present in the body for more than 10 days.
Metabolism/Excretion : Donepezil hydrochloride is excreted in the urine as a prototype or is metabolized by the cytochrome P450 system to a variety of metabolites, some of which have not been identified. After administration of a single dose of 14C-labeled donepezil hydrochloride 5 mg, plasma radioactivity (expressed as a percentage of the dose administered), was predominantly the prototype of donepezil hydrochloride (30%), 6-O-desmethyl donepezil (11%, the only metabolite with similar activity to donepezil hydrochloride), denepezil-cis-N-oxide (9%) , 5-O-desmethyl donepezil (7%) and the glucuronide conjugate of 5-O-desmethyl donepezi (3%). Approximately 57% of the total radioactivity was seen to be recovered from urine (with 17% being unconverted donepezil) and 14.5% from feces, suggesting biotransformation and urinary excretion as the major routes of elimination. There is no evidence of hepatic-intestinal circulation of donepezil hydrochloride and/or its metabolites. Plasma donepezil concentration decreases with a half-life of 70 hours. There were no clinically significant differences in the effects of gender, race, and smoking history on plasma donepezil hydrochloride concentrations. The pharmacokinetics of donepezil have not been formally studied in healthy elderly or Alzheimer’s disease patients; however, the mean plasma concentrations in patients were similar to values in younger healthy volunteers.
Indications
Treatment of mild or moderate symptoms of Alzheimer’s type dementia.
Dosage
Adults/Elderly: Initial treatment with 5 mg/day orally once a day at bedtime. 5 mg/day should be maintained for at least 1 month to evaluate early clinical response and to achieve steady-state blood concentrations of donepezil hydrochloride. After 1 month of treatment with 5 mg/day and clinical evaluation, the dose may be increased to 10 mg/day once a day. The maximum recommended dose is 10 mg; doses greater than 10 mg/day have not been clinically tested. After discontinuation of therapy, the efficacy of this drug gradually decreases without rebound from discontinuation of therapy.
Persons with impaired renal function and mild to moderate hepatic impairment: Elimination of donepezil hydrochloride is not affected and therefore a similar dosing regimen may be used in these patients.
Children : This drug is not recommended for use in children.
Adverse reactions
The most common adverse reactions (incidence ≥ (greater than or equal to) 5% and twice that of the placebo group) were diarrhea, muscle cramps, malaise, nausea, vomiting, and insomnia. Other common adverse reactions (incidence ≥ (greater than or equal to) 5% and ≥ (greater than or equal to) the placebo group) were headache, pain, accidental injury, common cold, abdominal organ disorders, and dizziness. Syncope, bradycardia and, rarely, sinoatrial block, atrioventricular block and epilepsy have also been reported.
Degeneration of liver function including hepatitis has hardly been reported. Discontinuation of this product should be considered in the event of unexplained hepatic degeneration. Psychiatric disturbances including hallucinations, irritability, and aggressive behavior have been reported. Resolution is by dose reduction or discontinuation of treatment. There have also been some reports of anorexia, gastric and duodenal ulcers, and gastrointestinal bleeding. A slight increase in blood creatine kinase concentrations may be seen.
Contraindications
Contraindicated in patients with hypersensitivity to donepezil hydrochloride, piperidine derivatives, or excipients in the formulation. Contraindicated in pregnant women.
Precautions
Treatment with this product should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s type dementia. Diagnosis is made by accepted criteria, and treatment with donepezil should be initiated only if the patient has a reliable caregiver who can regularly monitor the patient’s medication intake. Treatment may be continued for as long as the benefit to the patient persists. The response to donepezil cannot be predicted for each patient. It has not been fully observed in those patients with severe Alzheimer’s type dementia, other types of dementia or other types of memory impairment (e.g. age-related cognitive deterioration).
Anesthesia This drug is a cholinesterase inhibitor and may enhance the muscle relaxing effects of succinylcholine-type drugs during anesthesia.
Cardiovascular System Cholinesterase inhibitors may have vagal-like effects on heart rate (e.g., bradycardia) due to their pharmacological effects, and particular attention should be paid to patients with sick sinus syndrome or other supraventricular cardiac conduction disorders. Syncope and seizures have been reported. Special attention should be paid to patients with heart block or prolonged sinus gaps.
Digestive System Patients at increased risk for ulcer disease, such as those with a history of ulcer disease or in combination with NSAIDs, should be monitored for symptoms. However, in clinical trials of this drug, no increased incidence of peptic ulcers or gastrointestinal bleeding was seen compared to placebo.
Genitourinary system Cholinomimetic drugs may cause impaired bladder drainage, but this effect was not seen in clinical trials with this drug.
Neurological System Cholinomimetic effects may cause grand mal seizures, but seizures may also be a manifestation of Alzheimer’s disease.
Cholinesterase inhibitors should be used with caution in patients with a history of asthma or obstructive pulmonary disease because of their cholinergic effects. Avoid the use of other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system when taking this product.
Effects on the ability to drive and operate machinery Alzheimer’s type dementia itself may affect the ability to drive or operate machinery. In addition, donepezil can cause weakness, dizziness and muscle spasms, mainly when starting the drug or increasing the dose of the drug. The patient’s ability to continue driving and operating complex machines should be determined by his or her condition.
For pregnant and lactating women
No teratogenicity was found in teratogenic experiments in pregnant rats at approximately 80 times the human dose and in rabbits at 50 times the human dose. However, in experiments in pregnant rats at 50 times the human dose, there was a slight increase in stillbirths when the drug was administered from day 17 of gestation to day 20 postpartum. There was a mild decrease in litter survival at 4 days postpartum, but no abnormal effects were observed at the next lower dose of approximately 15 times the human dose. Donepezil should not be used during pregnancy. It is not known whether donepezil hydrochloride is secreted through women’s milk and has not been tested in lactating women. Therefore, women taking donepezil should not breastfeed.
Drug Interactions
Clinical experience with the application of donepezil is currently limited, and because of this, not all possible interactions may have been documented, so new, unknown interactions with donepezil may occur.
Neither donepezil hydrochloride and/or any of its metabolites inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. The metabolism of donepezil hydrochloride was not affected by concomitant administration of digoxin or cimetidine.
In vitro in vivo assays have shown that isoenzyme 3A4 of the cytochrome P450 system and isoenzyme 2D6, which is minimally involved, are associated with the metabolism of donepezil. In vitro drug-drug interaction studies have shown that ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6, respectively, inhibit the metabolism of donepezil. Thus, these drugs and other inhibitors of CYP3A4, such as itraconazole and erythromycin, and inhibitors of CYP2D6, such as fluoxetine, are able to inhibit the metabolism of donepezil. In studies conducted on healthy volunteers, ketoconazole increased the mean concentration of donepezil by approximately 30%. Enzyme inducers such as rifampin, phenytoin sodium, carbamazepine and alcohol may decrease the concentration of donepezil. Because the extent of the inhibitory or inducing effect is not known, the combination of similar drugs should be applied with great caution.
Donepezil hydrochloride has the potential to interact with anticholinergic drugs and to have synergistic effects with co-therapeutic agents such as succinylcholine, other neuromuscular blockers, cholinergic agonists or beta-blockers (which affect myocardial conduction).
Overdose
The LD50 of a single oral dose of donepezil hydrochloride in mice and rats was 45 and 32 mg/kg, or 225 and 160 times the recommended maximum human dose of 10 mg/day, respectively. Dose-related signs of cholinergic excitation observed in animals include reduced spontaneous movements, prone position, waddling gait, lacrimation, clonic convulsions, respiratory depression, salivation, constricted pupils, muscle bundle tremor, and decreased body surface temperature.
Overdose with cholinesterase inhibitors can cause cholinergic crisis, manifested by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions, and possibly progressive muscle weakness, which can be fatal if respiratory muscles are involved.
Treatment of patients with overdose should be done using general supportive therapy and giving tertiary amine anticholinergics such as atropine as an antidote. Atropine sulfate given intravenously is recommended, depending on the response, with the first doses of 1 mg and 2 mg given intravenously, followed by dosing based on clinical presentation. Atypical blood pressure and heart rate responses have been reported in combination with other cholinomimetics, such as with the quaternary anticholinergic Glycopyrrolate, and it is unclear whether donepezil hydrochloride and/or its metabolites can be cleared by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).