Date of approval.
Date of revision.
Donepezil Hydrochloride Orally Disintegrating Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Donepezil Hydrochloride Orally Disintegrating Tablets
English name: Donepezil Hydrochloride Orally Disintegrating Tablets
Hanyu Pinyin: Yansuan Duonaipaiqi Koubengpian
Ingredients
The main ingredient of this product is Donepezil Hydrochloride
Chemical name: (±)-2-[(1-benzyl-4-piperidinyl)methyl]-5,6-dimethoxy-1-indanone hydrochloride
Chemical structure formula.
Molecular formula: C24H29NO3-HCl
Molecular weight: 415.95
【Properties】.
This product is white round shallow arc tablet (5mg specification) or light yellow round shallow arc tablet (10mg specification).
Indications】
For the treatment of mild or moderate symptoms of Alzheimer’s disease.
Specification
(1) 5mg (2) 10mg
Dosage and Administration
Take orally.
Adults/elderly: Initial treatment dosage is 5mg (as Donepezil Hydrochloride) once a day. This product should be taken orally at night before bedtime. Depending on patient preference, the product should be placed on the tongue and swallowed with or without water of your choice after it disintegrates. A dose of 5 mg a day should be maintained for at least one month to evaluate early clinical response and to achieve steady-state blood concentrations of donepezil hydrochloride. After one month of treatment with 5 mg a day and clinical evaluation, the dose may be increased to 10 mg (as donepezil hydrochloride) once a day. The recommended maximum daily dose is 10 mg; doses greater than 10 mg a day have not been clinically tested.
The efficacy of donepezil hydrochloride gradually decreases after discontinuation of treatment.
2. Hepatic/renal insufficiency.
For 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, exposure to this product is increased (see [Pharmacokinetics]) and appropriate dose adjustment is recommended based on individual tolerance. There are no clinical data on the use of this drug in patients with severe hepatic insufficiency.
Adverse reactions]
The most common adverse events were diarrhea, muscle cramps, malaise, nausea, vomiting, and insomnia.
Non-case reported adverse reactions are listed below according to system organ classification and frequency. 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 (cannot be estimated based on available data).
Extremely common Common Occasional Rare Infections and infections Common cold Metabolic and nutritional Anorexia Mental Hallucinations**
Irritability**
Aggressive behavior** Central nervous syncope*
Dizziness
Insomnia Seizures* Extrapyramidal symptoms Heart Bradycardia Sinus atrioventricular block
Atrioventricular block Gastrointestinal diarrhea
Nausea and vomiting
Gastrointestinal dysfunction Gastrointestinal bleeding
Gastric and duodenal ulcers Hepatobiliary Liver dysfunction, including hepatitis*** Skin and subcutaneous tissue Rash
Pruritus Skeletal muscle, connective tissue and bone Muscle cramps Renal and urinary system Urinary incontinence Generalized headache Weakness
Pain Laboratory tests Slightly elevated blood creatine kinase concentrations Injury and poisoning Accidental injury * Syncope and seizures have been reported and the possibility of heart block or prolonged sinus arrest should be considered in patients presenting with such symptoms (see [Precautions]).
**Symptoms of psychiatric disorders (hallucinations, irritability, aggressive behavior) have been reported to improve with dose reduction or discontinuation.
***If unexplained hepatic dysfunction occurs, discontinuation of this product should be considered.
[Contraindicated].
Contraindicated in patients with a history of hypersensitivity to donepezil hydrochloride, piperidine derivatives, or excipients in the formulation.
Precautions】
Treatment with donepezil hydrochloride should be initiated and supervised by a physician experienced in the diagnosis and treatment of Alzheimer’s disease. It should be prescribed by recognized criteria (e.g., the American Psychiatric Association’s revised
Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM IV), International Classification of Diseases (10th edition) (ICD 10)) for diagnosis. Donepezil treatment should be initiated only if the patient has a reliable caregiver and can be monitored regularly for medication intake. 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 is no longer present. The response of each patient to donepezil is unpredictable.
The effectiveness of donepezil hydrochloride has not been fully observed in those patients with severe Alzheimer’s disease and other types of dementia or other types of memory impairment (e.g., age-related cognitive impairment).
Anesthesia: Donepezil hydrochloride 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 pharmacologic effects, and special attention should be given to patients with “sick sinus syndrome” or other supraventricular cardiac conduction disorders (e.g., sinus or atrioventricular block).
Syncope and seizures have been reported, and patients with these symptoms should be especially alert to the possibility of heart block or prolonged sinus arrest.
Digestive system: Patients at increased risk for ulcer disease, such as those with a history of ulcer disease or those on non-steroidal anti-inflammatory drugs (NSAIDs), should be monitored for symptoms. However, in clinical trials with donepezil hydrochloride, no increase in the incidence of peptic ulcers or gastrointestinal bleeding was seen compared with placebo.
Genitourinary system: Cholinomimetic drugs may cause bladder outlet obstruction, but this effect was not seen in clinical trials with donepezil hydrochloride.
Neurological: Cholinomimetic drugs may cause grand mal seizures. However, seizures may also be a manifestation of Alzheimer’s disease.
Cholinomimetics have the potential to exacerbate or induce extrapyramidal symptoms.
Respiratory system: Because of their cholinomimetic effects, cholinesterase inhibitors 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.
Severe hepatic insufficiency: There are no clinical data on the use of donepezil in patients with severe hepatic insufficiency.
Driving and operating machinery: Donepezil has a mild to moderate effect on the ability to drive a car and operate machinery. The dementia itself may affect driving a car or operating a machine. In addition, donepezil may cause weakness, dizziness, and muscle cramps when the drug is started or when the drug dose is increased. Patients taking donepezil should be routinely evaluated by the treating physician for their ability to continue to drive a car or operate complex machinery.
Mortality in clinical trials of vascular dementia
To study the therapeutic effects of donepezil hydrochloride in vascular dementia (VaD), three 6-month clinical trials were conducted, enrolling patients who met the NINDS-AIREN diagnostic criteria. The National Institute of Neurological Disorders and Stroke and the Swiss International Association for Neuroscience Research (NINDS-AIREN) diagnostic criteria were used to identify patients with dementia caused by vascular disease alone and to exclude patients with Alzheimer’s disease. In the first study, the mortality rate was 1.0% (2 cases/198 cases) in the 5 mg donepezil hydrochloride group, 2.4% (5 cases/206 cases) in the 10 mg donepezil hydrochloride group, and 3.5% (7 cases/199 cases) in the placebo group. In the second study, the mortality rate was 1.9% (4 cases/208 cases) in the 5 mg donepezil hydrochloride group, 1.4% (3 cases/215 cases) in the 10 mg donepezil hydrochloride group, and 0.5% (1 case/193 cases) in the placebo group. In the third study, the mortality rate was 1.7% (11 cases/648 cases) in the 5 mg donepezil hydrochloride group and 0% (0 cases/326 cases) in the placebo group. The combined mortality rate in the three VaD clinical trials was (1.7%) in the donepezil hydrochloride group, which was higher than in the placebo group (1.1%), but this difference was not statistically significant. The majority of deaths in patients in the donepezil hydrochloride or placebo groups were due to various vascular complications, which is to be expected in older adults with underlying vascular disease. An analysis of all serious nonfatal or fatal vascular events showed no statistically significant difference in the incidence of vascular events between the donepezil hydrochloride and placebo groups.
In the combined studies of Alzheimer’s disease (n=4146), when these studies were analyzed in combination with studies of other types of dementia, including vascular dementia (n=6888), mortality was higher in the placebo group than in the donepezil hydrochloride group.
[For pregnant and lactating women].
Pregnancy.
There are no adequate clinical data on the use of the drug in pregnant women.
Animal studies have not shown teratogenic effects of donepezil, but have shown perinatal and postnatal toxicity (see [Pharmacology and Toxicology]). The potential risk to humans is not known.
It should not be used in pregnant women unless there is a clear indication that the drug must be administered.
Lactation.
Donepezil is excreted in rat milk. It is not known whether it is excreted in human milk and no studies have been performed in nursing women. Therefore, women taking this product should not breastfeed.
Pediatric use
This product is not recommended for use in children.
Geriatric use
See [Dosage].
Drug Interactions
Neither donepezil hydrochloride nor any of its metabolites inhibit the metabolism of theophylline, warfarin, cimetidine, or digoxin in humans. 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 isoenzymes 3A4 and 2D6 of the cytochrome P450 system, 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 rifampicin, phenytoin, 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. Donepezil hydrochloride may interfere with the treatment with anticholinergic drugs. There is a possibility of synergistic effects when combined with drugs such as succinylcholine, other neuromuscular junction blockers or choline agonists or beta-blockers (which affect cardiac conduction).
Drug overdose]
The LD50 of a single oral dose of donepezil hydrochloride in mice and rats were 45 and 32 mg/kg, respectively, which were 225 and 160 times the maximum recommended 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, fasciculus tremors, and decreased body surface temperature.
Overdose of cholinesterase inhibitors can cause cholinergic crisis, manifested by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, fainting and convulsions. There may be progressive muscle weakness, which can be fatal if respiratory muscles are involved.
General supportive therapy should be used to treat patients with overdose. In case of overdose, tertiary amine anticholinergics such as atropine are used as antidotes. Atropine sulfate is recommended to be given intravenously and titrated until it takes effect. The first dose of 1.0 mg to 2.0 mg should be given intravenously, followed by administration according to clinical manifestations. Atypical blood pressure and heart rate responses have been reported in combination 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).
[Clinical Trials].
Alzheimer’s disease
In clinical trials, donepezil hydrochloride was administered orally at 5 mg or 10 mg once a day to patients with Alzheimer’s disease, and acetylcholinesterase activity (as measured by erythrocyte membranes) was inhibited by 63.6% and 77.3%, respectively, at steady state after administration. The inhibitory effect of donepezil hydrochloride on erythrocyte acetylcholinesterase (AChE) correlated with changes in the scores of the ADAS-cog scale (a scale for measuring cognitive function). This scale is more sensitive in the measurement of cognitive function. Whether donepezil hydrochloride has the potential to alter the underlying neuropathological processes of the disease has not been studied. Therefore, donepezil hydrochloride cannot be considered to have a role in the progressive course of the disease.
Four placebo-controlled clinical trials looked at the efficacy of donepezil hydrochloride in the treatment of Alzheimer’s disease, two over a 6-month period and two over a 1-year period.
In the 6-month clinical trials, three efficacy indicators were combined to analyze the treatment with donepezil: the ADAS-cog scale (a measure of cognitive function), the CIBIC-plus scale (a measure of overall functioning) and the ADL subscale of the CDR scale (a measure of social affairs, family, hobbies and personal care skills).
Patients who met the following criteria were considered to be responding to treatment.
Responding = improvement of at least 4 points on the ADAS-cog scale
No deterioration in CIBIC-plus scale scores
No worsening of scores on the ADL subscale of the CDR
% response Intention-to-treat set n=365 Assessable set n=352 Placebo group 10% 10% 5mg dose group 18%*18%*10mg dose group 21%*22%***p < 0.05
**p < 0.01
The percentage of patients judged to be responding to treatment increased in the donepezil hydrochloride treatment group, and this increase was statistically significant and dose dependent.
[Pharmacology and Toxicology].
Pharmacological effects.
Donepezil hydrochloride is a specific and reversible acetylcholinesterase inhibitor. Acetylcholinesterase is the major cholinesterase in the brain. In in vitro tests, the inhibitory effect of donepezil hydrochloride on acetylcholinesterase was 1000 times stronger than that on butyrylcholinesterase (mainly found outside the central nervous system).
Toxicological studies.
Extensive animal testing has shown that the drug has few effects other than a pharmacological effect of cholinergic neuroexcitation (see [Drug Overdose]). Donepezil hydrochloride was not found to be mutagenic in bacterial and mammalian cell mutagenesis assays, and some fracture-inducing effects were observed in in vitro experiments, but only at concentrations that were significantly toxic to cells and at concentrations above 3000 times the steady-state blood concentration in patients in clinical trials. In an in vivo micronucleus model in mice, no fracture-inducing or other genotoxic effects of donepezil hydrochloride were observed. In long-term carcinogenicity studies in rats and mice, 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 stillbirth and early survival of the litter when given to pregnant rats at 50 times the human dose (see [Pregnancy and Lactation]).
Pharmacokinetics
Absorption: Maximum 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. Steady state will be reached slowly after multiple daily doses of single dose administration. Steady state is generally reached within 3 weeks after the start of treatment. After steady state, plasma concentrations and corresponding pharmacodynamic activity of donepezil hydrochloride 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 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 mass balance studies in healthy 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.
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 a single dose of 5 mg of 14C-labeled donepezil hydrochloride, plasma radioactivity (expressed as a percentage of the dose administered), was predominantly the prototype donepezil hydrochloride (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.
Gender, race and smoking history have no clinically significant effect on plasma concentrations of donepezil hydrochloride. The pharmacokinetics of donepezil have not been formally studied in healthy elderly or in patients with Alzheimer’s disease or vascular dementia; however, mean plasma concentrations in patients were similar to values in young healthy volunteers.
In patients with mild to moderate hepatic insufficiency, steady-state blood concentrations of donepezil were increased, with a 48% increase in mean area under the drug-time curve (AUC) and a 39% increase in mean maximum blood concentration (Cmax) (see [Dosage]).
Storage
Store at room temperature (10~30℃) under seal.
Package
Aluminum-plastic packaging, 10 tablets/plate, 3 plates/box.
Expiration date
36 months
Execution Standard
Approval number】
【Marketing license holder
Company name: Zhejiang Haisheng Pharmaceutical Co.
Registered Address: No. 46, Waisha Road, Jiaojiang District, Taizhou City, Zhejiang Province
Postal Code: 318000
Telephone number: 0576-88827987
Fax number: 0576-88827887
Web
Address: www.hisunpharm.com
Manufacturer
Company name: Zhejiang Haisheng Pharmaceutical Co.
Address: No.1, Haizheng Avenue, Jiaojiang District, Taizhou City, Zhejiang Province
Postal Code: 318000
Telephone number: 0576-88827987
Fax number: 0576-88827887
Web
Address: www.hisunpharm.com