Approval date: 07/11/2001
Revision date: 04/16/2004
January 22, 2010
November 05, 2010
August 05, 2011
Year Month Day
Donepezil Hydrochloride Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician.
Drug Name
Generic name: Donepezil Hydrochloride Tablets
English name: Donepezil Hydrochloride Tablets
Hanyu Pinyin: Yansuan Duonaipaiqi Pian
Ingredients
The main ingredient of this product is: Donepezil Hydrochloride
Chemical name: (±)-2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride monohydrate.
Structural formula.
Molecular formula: C24H29NO3-HCl-H2O
Molecular weight: 433.98
Characteristic】.
This product is a film-coated tablet, which appears white or off-white after removing the coating.
Indications
Treatment of mild, moderate or severe symptoms of Alzheimer’s disease.
Specification
5 mg (based on C24H29NO3-HCl)
Dosage and Administration
Take orally.
1. Adults/elderly: Initial therapeutic dosage of 5 mg (as donepezil hydrochloride) once a day. Donepezil hydrochloride should be taken orally at night before bedtime. The 5 mg once-a-day dose should be maintained for at least one month to evaluate the early clinical response and to achieve steady-state blood levels of donepezil hydrochloride. After one month of 5 mg a day treatment and clinical evaluation, the dose of donepezil hydrochloride may be increased to 10 mg once a day (as donepezil hydrochloride).
-After discontinuation of treatment, the efficacy of donepezil hydrochloride gradually decreases. No rebound after discontinuation of treatment.
2. Hepatic/renal insufficiency.
In patients with renal insufficiency, donepezil hydrochloride is administered in a similar manner to normal subjects as clearance of donepezil hydrochloride is not affected by this.
In patients with mild to moderate hepatic insufficiency, due to possible effects (see Pharmacokinetics), appropriate dose adjustments are recommended based on individual tolerance. There are no clinical data on the use of the drug in patients with severe hepatic insufficiency.
Adverse reactions]
The most common adverse reactions include diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia.
The following is a list of adverse reactions other than individual cases according to their frequency of occurrence. The frequency of adverse reactions is defined as: very common (≥1/10), common (≥1/100, <1/10), occasional (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000) and unknown (not known from available data).
Very common: diarrhea, nausea, headache.
Common: common cold, anorexia, vomiting, rash, pruritus, syncope*, hallucinations**, irritability**, aggressive behavior**, vertigo, insomnia, abdominal discomfort, muscle cramps, urinary incontinence, malaise, pain, accidental injury, abnormal dreams and nightmares.
Occasionally: seizures*, bradycardia, gastrointestinal bleeding, gastric and duodenal ulcers, hypersalivation, slight elevation of blood creatine kinase concentration.
Rare: extrapyramidal symptoms, sinusoidal block, atrioventricular block, hepatic dysfunction (including hepatitis***).
Very rare: nerve blocker malignant syndrome and rhabdomyolysis.
*The possibility of heart block or long sinus intervals occurring should be considered when examining patients for syncope or seizures.
**Hallucinations, abnormal dreaming, nightmares, agitation, and aggressive behavior resolve after dose reduction or treatment discontinuation.
*** Discontinuation of donepezil hydrochloride should be considered if unexplained hepatic dysfunction occurs.
**** has reported the occurrence of rhabdomyolysis independently of neuroblocker malignant syndrome and has a close transient relationship with donepezil initiation of treatment or dose increase.
Contraindications
Contraindicated in patients with a history of hypersensitivity to donepezil hydrochloride, piperidine derivatives, or excipients in the formulation.
Not for use in pregnant women.
This preparation contains lactose. It is contraindicated in patients with rare genetic problems such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
[Precautions].
Treatment with donepezil hydrochloride should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s disease. The diagnosis should be established by recognized criteria (e.g. DSM 5, ICD10). Donepezil therapy should be initiated only if the patient has a reliable caregiver and can be monitored regularly for medication. Treatment can be continued as long as the benefit to the patient remains. Therefore, the clinical efficacy of donepezil should be reassessed periodically. Discontinuation of treatment should be considered when the benefit of treatment no longer exists. The response of each patient to donepezil cannot be predicted. The effect of donepezil hydrochloride in patients with other types of dementia or memory impairment (e.g., age-related cognitive impairment) has not been fully observed.
Anesthesia: Donepezil hydrochloride is a cholinesterase inhibitor and may enhance the muscle relaxing effects of succinylcholine-type drugs during anesthesia.
Cardiovascular: Cholinesterase inhibitors may have vagal-like effects on heart rate (e.g., bradycardia) due to their pharmacologic effects, and particular attention should be paid to patients with “sick sinus syndrome” or other supraventricular cardiac conduction disorders such as sinus or atrioventricular block.
*Syncope and seizures have been reported. In these patients, there is a special need to be alert for the possibility of heart block or sinus arrest.
**Dose should be reduced or discontinued if symptoms of mental disturbance (hallucinations, irritability, aggressive behavior) occur.
Effects on the ability to drive and operate machinery: Dementia may affect the ability to drive or operate machinery. In addition, mainly when starting the drug or increasing the dose of the drug, donepezil may cause weakness, dizziness and muscle cramps. For patients taking donepezil, the treating physician should routinely assess their ability to drive a car or operate complex machinery.
Digestive system: Patients at increased risk for ulcer disease, such as those with a history of ulcer disease or co-administration of non-steroidal anti-inflammatory drugs (NSAIDS), should be monitored for symptoms. However, in clinical trials with donepezil hydrochloride tablets, no increase in the incidence of peptic ulcers or gastrointestinal bleeding was observed compared to placebo.
Genitourinary system: Cholinomimetic drugs may cause bladder outlet obstruction, but this effect was not seen in clinical trials with Donepezil Hydrochloride Tablets.
Neurological: Cholinomimetic effects may cause grand mal seizures. However, epilepsy may also be a manifestation of Alzheimer’s disease.
Cholinomimetic agents have the potential to exacerbate or induce extrapyramidal symptoms.
Neuroblocker malignant syndrome (NMS): NMS, a potentially life-threatening disorder characterized by hypothermia, muscle rigidity, dysautonomia, altered consciousness, and elevated serum creatine phosphokinase levels, has rarely been reported in association with donepezil administration, especially in patients receiving comorbid antipsychotics. Other signs of the disease may include myoglobinuria (rhabdomyolysis) and acute renal failure. Treatment should be discontinued if a patient develops signs and symptoms suggestive of NMS or unexplained hyperthermia not accompanied by other clinical manifestations of NMS.
Respiratory: Because of its cholinomimetic effect, it should be used with caution in patients with a history of asthma or obstructive pulmonary disease. Avoid co-administration of other acetylcholinesterase inhibitors, agonists or antagonists of the cholinergic system when taking Donepezil Hydrochloride Tablets.
Severe hepatic insufficiency: There is no clinical information on the use of the drug in patients with severe hepatic insufficiency.
*** Discontinuation of donepezil hydrochloride should be considered in the event of unexplained hepatic dysfunction.
In the combined studies of Alzheimer’s disease (n=4146), the placebo group had a higher mortality rate than the donepezil hydrochloride group when these studies were analyzed in combination with other dementia studies including vascular dementia (n=6888). There is no evidence of increased mortality for mild, moderate or severe Alzheimer’s disease for the approved indications.
[Pregnant and lactating women use].
1. Pregnancy: Teratogenicity was not found in the teratogenic experiments performed in pregnant rats at approximately 80 times the human dose and in rabbits at 50 times the human dose. However, in experiments conducted in pregnant rats at 50 times the human dose, there was a slight increase in stillbirths from day 17 of gestation to day 20 postpartum, and a slight decrease in the survival rate of the litter 4 days postpartum. However, at the next lower dose of approximately 15 times the human dose, no abnormal effects were observed. There are no clinical data on the use of donepezil in pregnant women. Therefore, this product is contraindicated in pregnant women.
2. There is no information on the safety and efficacy of the drug in nursing mothers, therefore, women taking this product should not breastfeed.
Pediatric use]
Donepezil hydrochloride tablets are not recommended for use in children.
Geriatric use
See [Dosage and Administration], item 1 for details.
Drug Interactions
Donepezil hydrochloride and/or any of its metabolites do not inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in the human body. The metabolism of donepezil hydrochloride is not affected by concomitant administration of digoxin or cimetidine. In vitro tests have shown that the metabolism of donepezil is associated with isozymes 3A4 and 2D6 of cytochrome oxidase P450, with the latter being minimally involved. 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 and other inhibitors of CYP3A4 such as itraconazole and erythromycin, as well as inhibitors of CYP2D6 such as fluoxetine, 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 effects is unknown, the combination of similar drugs should be used with great caution. There may be interactions between donepezil hydrochloride and anticholinergic drugs. There may be synergistic effects when combined with drugs such as succinylcholine, other neuromuscular junction blockers or cholinergic agonists or beta-blockers (which affect myocardial conduction).
Drug overdose]
Overdose of cholinesterase inhibitors can cause cholinergic crisis, manifested by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. There may be progressive muscle weakness, which can be fatal if the respiratory muscles are involved.
Treat patients with overdose with general supportive therapy. For donepezil hydrochloride overdose, use a tertiary amine anticholinergic such as atropine as an antidote. It is recommended that atropine sulfate be given intravenously titrated to onset of action: 1.0 mg to 2.0 mg intravenously for the first dose, then administered according to clinical manifestations. There are reports of insignificant blood pressure and heart rate responses when combined with other cholinomimetic agents, such as Glycopyrrolate, a quaternary anticholinergic. It is not known whether donepezil hydrochloride and/or its metabolites can be cleared by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
Pharmacology and Toxicology
Pharmacological effects
The pathogenesis of dementia symptoms in Alzheimer’s disease is currently thought to be partly related to hypocholinergic neurotransmission function. Donepezil hydrochloride may exert its therapeutic effect by enhancing the function of cholinergic nerves. It reversibly inhibits the hydrolysis of acetylcholine by acetylcholinesterase, thereby increasing the concentration of acetylcholine. If the above mechanism of action is speculated, the effect of donepezil may diminish as the disease progresses and the number of functionally intact cholinergic neurons tapers off. There is no evidence that donepezil can alter the underlying course of dementia.
Toxicological studies
Reproductive toxicity.
Fertility was not affected in rats given donepezil at 10 mg/kg/day (approximately 8 times the maximum recommended human dose, converted to body surface area). No significant teratogenic effects were observed in pregnant rats and rabbits given donepezil at 16 and 10 mg/kg/day (approximately 13 and 16 times the recommended maximum human dose, respectively, based on body surface area). In another study, the number of stillbirths was slightly increased and the viability of the offspring was slightly decreased within 4 days after delivery when donepezil was given continuously from day 17 of gestation to day 20 after delivery at 10 mg/kg/day (approximately 8 times the maximum recommended human dose based on body surface area).
Genotoxicity.
Donepezil was not seen to be mutagenic in the Ames bacterial reversion mutation test. Donepezil was seen to have a cleavage-inducing effect in the Chinese hamster lung cell chromosome aberration assay. Donepezil did not induce cleavage in the mouse micronucleus assay.
Carcinogenicity: There is no information on the carcinogenicity of donepezil.
Pharmacokinetics
1. Absorption: The highest plasma concentration is reached after about 3-4 hours of oral administration. Plasma concentration and area under the drug-time curve are proportional to the dose. The elimination half-life is about 70 hours, so steady state will be reached gradually after multiple daily doses of single dose administration. Steady state is generally reached within 3 weeks of treatment initiation. After steady state, plasma donepezil hydrochloride concentrations and corresponding pharmacodynamic activity vary minimally throughout the day.
Diet has no effect on the absorption of donepezil hydrochloride.
2. Distribution: Approximately 95% of donepezil hydrochloride is bound to human plasma proteins. The plasma protein binding of its active metabolite, 6-oxo-desmethyl donepezil, is not known. 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 5 mg dose of 14C-labeled donepezil hydrochloride, suggesting that donepezil hydrochloride and/or its metabolites may be present in the body for more than 10 days.
3. Metabolism/Excretion: Donepezil hydrochloride is excreted as a prototype by urine or metabolized by the cytochrome oxidase P450 system to a variety of metabolites, some of which have not been identified. After a single dose of 5 mg of 14C-labeled donepezil hydrochloride, plasma radioactivity (expressed as a percentage of the dose administered), was predominantly donepezil hydrochloride prototype (30%), 6-oxo-desmethyl-donepezil (11%-the only metabolite with similar activity to donepezil hydrochloride), donepezil-cis-N-oxide ( 9%), 5-oxo-demethyldonepezil (7%) and glucuronide conjugate of 5-oxo-demethyldonepezil (3%). Approximately 57% of the total radioactivity was 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. The effects of gender, race, and smoking history on plasma donepezil hydrochloride concentrations were not clinically significant. 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 those values in younger healthy volunteers. In patients with mild to moderate hepatic insufficiency, steady-state blood concentrations of donepezil were increased: the mean area under the drug-time curve (AUC) was increased by 48% and the mean maximum blood concentration (Cmax) was increased by 39%. (See [Dosage and Administration])
Storage
Store at room temperature.
Packaging
Packed in cellophane/aluminum/polyethylene pharmaceutical compound film, 7 tablets/plate/box.
Expiration date
24 months
Execution standard
Approval number】
State Drug Registration Number】 H20010723.
【Manufacturer】
Enterprise name: Chongqing Shine Pharmaceutical Co.
Production Address: No. 70, Keyuan 4 Street, Jiulongpo District, Chongqing
Postal Code: 400041
Telephone number: 023-68690872 (quality complaints)
023-66096667 (Sales)
Fax number: 023-68622365
Web address: www.zhienyaoye.com