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英文药名: ARICEPT(donepezil hydrochloride)tablets 中文药名: 盐酸多奈哌齐片 生产厂家: Eisai Inc.
FULL PRESCRIBING INFORMATION
1. INDICATIONS AND USAGE ARICEPT is indicated for the treatment of dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's disease. 2. DOSAGE AND ADMINISTRATION ARICEPT should be taken in the evening, just prior to retiring. ARICEPT can be taken with or without food. The 23mg tablet should not be split, crushed or chewed because this may increase its rate of absorption. Allow ARICEPT ODT to dissolve on the tongue and follow with water. 2.1. Mild to Moderate Alzheimer's Disease The dosages of ARICEPT shown to be effective in controlled clinical trials are 5mg and 10mg administered once per day. The higher dose of 10mg did not provide a statistically significantly greater clinical benefit than 5mg. There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10mg of ARICEPT might provide additional benefit for some patients. Accordingly, whether or not to employ a dose of 10mg is a matter of prescriber and patient preference. 2.2. Moderate to Severe Alzheimer's Disease ARICEPT has been shown to be effective in controlled clinical trials at doses of 10mg and 23mg administered once daily. Results of a controlled clinical trial in moderate to severe Alzheimer's Disease that compared ARICEPT 23mg once daily to 10mg once daily suggest that a 23mg dose of ARICEPT provided additional benefit. 2.3. Titration The recommended starting dose of ARICEPT is 5mg once daily. Evidence from the controlled trials in mild to moderate Alzheimer's disease indicates that the 10mg dose, with a one week titration, is likely to be associated with a higher incidence of cholinergic adverse events compared to the 5mg dose. In open-label trials using a 6week titration, the type and frequency of these same adverse events were similar between the 5mg and 10mg dose groups. Therefore, because ARICEPT steady state is achieved about 15days after it is started and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of 10mg should not be administered until patients have been on a daily dose of 5mg for 4 to 6weeks. A dose of 23mg once daily can be administered once patients have been on a dose of 10mg once daily for at least 3months. 3. DOSAGE FORMS AND STRENGTHS ARICEPT is supplied as film-coated, round tablets containing 5mg, 10mg, or 23mg of donepezil hydrochloride. The 5mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side. ARICEPT ODT is supplied as round tablets containing either 5mg or 10mg of donepezil hydrochloride. The 5mg orally disintegrating tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side. 4. CONTRAINDICATIONS ARICEPT is contraindicated in patients with known hypersensitivity to donepezil hydrochloride or to piperidine derivatives. 5. WARNINGS AND PRECAUTIONS 5.1. Anesthesia ARICEPT, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.2. Cardiovascular Conditions Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Syncopal episodes have been reported in association with the use of ARICEPT. 5.3. Nausea and Vomiting ARICEPT, as a predictable consequence of its pharmacological properties, has been shown to produce diarrhea, nausea, and vomiting. These effects, when they occur, appear more frequently with the 10mg/day dose than with the 5mg/day dose, and more frequently with the 23mg dose than with the 10mg dose. Specifically, in a controlled trial that compared a dose of 23mg/day to 10mg/day in patients who had been treated with donepezil 10mg/day for at least three months, the incidence of nausea in the 23mg group was markedly greater than in the patients who continued on 10mg/day (11.8%vs. 3.4%, respectively), and the incidence of vomiting in the 23mg group was markedly greater than in the 10mg group (9.2%vs. 2.5%, respectively). The percent of patients who discontinued treatment due to vomiting in the 23mg group was markedly higher than in the 10mg group (2.9%vs. 0.4%, respectively). Although in most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT, patients should be observed closely at the initiation of treatment and after dose increases. 5.4. Peptic Ulcer Disease and GI Bleeding Through their primary action, cholinesterase inhibitors may be expected to increase gastric acid secretion due to increased cholinergic activity. Therefore, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g.,those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of ARICEPT in a dose of 5mg/day to 10mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Results of a controlled clinical study with 23mg/day showed an increase, relative to 10mg/day, in the incidence of peptic ulcer disease (0.4%vs. 0.2%) and gastrointestinal bleeding from any site (1.1%vs. 0.6%) 5.5. Weight Loss Weight loss was reported as an adverse event in 4.7% of patients assigned to ARICEPT in a dose of 23mg/day compared to 2.5% of patients assigned to 10mg/day. Compared to their baseline weights, 8.4% of patients taking 23mg/day were found to have a weight decrease of ≥7% by the end of the study, while 4.9% of patients taking 10mg/day were found to have weight loss of ≥7% at the end of the study. 5.6. Genitourinary Conditions Although not observed in clinical trials of ARICEPT, cholinomimetics may cause bladder outflow obstruction. 5.7. Neurological Conditions: Seizures Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity also may be a manifestation of Alzheimer's disease. 5.8. Pulmonary Conditions Because of their cholinomimetic actions, cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease. 6. ADVERSE REACTIONS 6.1. Clinical Studies Experience ARICEPT 5mg/day and 10mg/day Mild to Moderate Alzheimer's Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse events for the ARICEPT 5mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5mg/day to 10mg/day was higher at 13%. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table1.
Most Frequent Adverse Events Seen in Association with the Use of ARICEPT The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving 10mg/day and twice the placebo rate, are largely predicted by ARICEPT's cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue and anorexia. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification. There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. An open-label study was conducted with 269patients who received placebo in the 15 and 30-week studies. These patients were titrated to a dose of 10mg/day over a 6-week period. The rates of common adverse events were lower than those seen in patients titrated to 10mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5mg/day. See Table2 for a comparison of the most common adverse events following one and six week titration regimens.
Adverse Events Reported in Controlled Trials The events cited reflect experience gained under closely monitored conditions of clinical trials in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table3 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo. In general, adverse events occurred more frequently in female patients and with advancing age.
Other Adverse Events Observed During Clinical Trials ARICEPT has been administered to over 1700individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3months and more than 1000patients have been treated for at least 6months. Controlled and uncontrolled trials in the United States included approximately 900patients. In regards to the highest dose of 10mg/day, this population includes 650patients treated for 3months, 475patients treated for 6months and 116patients treated for over 1year. The range of patient exposure is from 1 to 1214days. Treatment emergent signs and symptoms that occurred during three controlled clinical trials and two open-label trials in the United States were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified COSTART dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 900patients from these trials who experienced that event while receiving ARICEPT. All adverse events occurring at least twice are included, except for those already listed in Tables2 or 3, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100patients; Infrequent adverse events - those occurring in 1/100 to 1/1000patients. These adverse events are not necessarily related to ARICEPT treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. No important additional adverse events were seen in studies conducted outside the United States. Body as a Whole:Frequent: influenza, chest pain, toothache; Infrequent: fever, edema face, periorbital edema, hernia hiatal, abscess, cellulitis, chills, generalized coldness, head fullness, listlessness. Cardiovascular System:Frequent: hypertension, vasodilation, atrial fibrillation, hot flashes, hypotension; Infrequent: angina pectoris, postural hypotension, myocardial infarction, AV block (first degree), congestive heart failure, arteritis, bradycardia, peripheral vascular disease, supraventricular tachycardia, deep vein thrombosis. Digestive System:Frequent: fecal incontinence, gastrointestinal bleeding, bloating, epigastric pain; Infrequent: eructation, gingivitis, increased appetite, flatulence, periodontal abscess, cholelithiasis, diverticulitis, drooling, dry mouth, fever sore, gastritis, irritable colon, tongue edema, epigastric distress, gastroenteritis, increased transaminases, hemorrhoids, ileus, increased thirst, jaundice, melena, polydipsia, duodenal ulcer, stomach ulcer. Endocrine System:Infrequent: diabetes mellitus, goiter. Hemic and Lymphatic System:Infrequent: anemia, thrombocythemia, thrombocytopenia, eosinophilia, erythrocytopenia. Metabolic and Nutritional Disorders:Frequent: dehydration; Infrequent: gout, hypokalemia, increased creatine kinase, hyperglycemia, weight increase, increased lactate dehydrogenase. Musculoskeletal System:Frequent: bone fracture; Infrequent: muscle weakness, muscle fasciculation. Nervous System:Frequent: delusions, tremor, irritability, paresthesia, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, nervousness, aphasia; Infrequent: cerebrovascular accident, intracranial hemorrhage, transient ischemic attack, emotional lability, neuralgia, coldness (localized), muscle spasm, dysphoria, gait abnormality, hypertonia, hypokinesia, neurodermatitis, numbness (localized), paranoia, dysarthria, dysphasia, hostility, decreased libido, melancholia, emotional withdrawal, nystagmus, pacing. Respiratory System:Frequent: dyspnea, sore throat, bronchitis; Infrequent: epistaxis, post nasal drip, pneumonia, hyperventilation, pulmonary congestion, wheezing, hypoxia, pharyngitis, pleurisy, pulmonary collapse, sleep apnea, snoring. Skin and Appendages:Frequent: pruritus, diaphoresis, urticaria; Infrequent: dermatitis, erythema, skin discoloration, hyperkeratosis, alopecia, fungal dermatitis, herpes zoster, hirsutism, skin striae, night sweats, skin ulcer. Special Senses:Frequent: cataract, eye irritation, vision blurred; Infrequent: dry eyes, glaucoma, earache, tinnitus, blepharitis, decreased hearing, retinal hemorrhage, otitis externa, otitis media, bad taste, conjunctival hemorrhage, ear buzzing, motion sickness, spots before eyes. Urogenital System:Frequent: urinary incontinence, nocturia; Infrequent: dysuria, hematuria, urinary urgency, metrorrhagia, cystitis, enuresis, prostate hypertrophy, pyelonephritis, inability to empty bladder, breast fibroadenosis, fibrocystic breast, mastitis, pyuria, renal failure, vaginitis. Severe Alzheimer's Disease Adverse Events Leading to Discontinuation The rates of discontinuation from controlled clinical trials of ARICEPT due to adverse events for the ARICEPT patients were approximately 12% compared to 7% for placebo patients. The most common adverse events leading to discontinuation, defined as those occurring in at least 2% of ARICEPT patients and at twice or more the incidence seen in placebo, were anorexia (2%vs. 1% placebo), nausea (2%vs. <1% placebo), diarrhea (2%vs. 0% placebo) and urinary tract infection (2%vs. 1% placebo). Most Frequent Adverse Events Seen in Association with the Use of ARICEPT The most common adverse events, defined as those occurring at a frequency of at least 5% in patients receiving ARICEPT and at twice or more the placebo rate, are largely predicted by ARICEPT's cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse events were often of mild intensity and transient, resolving during continued ARICEPT treatment without the need for dose modification. Adverse Events Reported in Controlled Trials Table4 lists adverse events that were reported in at least 2% of patients in placebo-controlled trials who received ARICEPT and for which the rate of occurrence was greater for patients treated with ARICEPT than with placebo.
Other Adverse Events Observed During Clinical Trials ARICEPT has been administered to over 600patients with severe Alzheimer's disease during clinical trials of at least 6months duration, including three double-blind placebo-controlled trials, two of which had an open label extension. All adverse events occurring at least twice are included, except for those already listed in Table4, COSTART terms too general to be informative, or events less likely to be drug related. Events are classified by body system using the COSTART dictionary and listed using the following definitions: Frequent adverse events - those occurring in at least 1/100patients; Infrequent adverse events - those occurring in 1/100 to 1/1000patients. These adverse events are not necessarily related to ARICEPT treatment and in most cases were observed at a similar frequency in placebo treated patients in the controlled studies. Body as a Whole:Frequent: abdominal pain, asthenia, fungal infection, flu syndrome; Infrequent: allergic reaction, cellulitis, malaise, sepsis, face edema, hernia. Cardiovascular System:Frequent: hypotension, bradycardia, ECG abnormal, heart failure; Infrequent: myocardial infarction, angina pectoris, atrial fibrillation, congestive heart failure, peripheral vascular disorder, supraventricular extrasystoles, ventricular extrasystoles, cardiomegaly. Digestive System:Frequent: constipation, gastroenteritis, fecal incontinence, dyspepsia; Infrequent: gamma glutamyl transpeptidase increase, gastritis, dysphagia, periodontitis, stomach ulcer, periodontal abscess, flatulence, liver function tests abnormal, eructation, esophagitis, rectal hemorrhage. Endocrine System:Infrequent: diabetes mellitus. Hemic and Lymphatic System:Frequent: anemia; Infrequent: leukocytosis. Metabolic and Nutritional Disorders:Frequent: weight loss, peripheral edema, edema, lactic dehydrogenase increased, alkaline phosphatase increased; Infrequent: hypercholesteremia, hypokalemia, hypoglycemia, weight gain, bilirubinemia, BUN increased, B12 deficiency anemia, cachexia, creatinine increased, gout, hyponatremia, hypoproteinemia, iron deficiency anemia, SGOT increased, SGPT increased. Musculoskeletal System:Frequent: arthritis; Infrequent: arthrosis, bone fracture, arthralgia, leg cramps, osteoporosis, myalgia. Nervous System:Frequent: agitation, anxiety, tremor, convulsion, wandering, abnormal gait; Infrequent: apathy, vertigo, delusions, abnormal dreams, cerebrovascular accident, increased salivation, ataxia, euphoria, vasodilatation, cerebral hemorrhage, cerebral infarction, cerebral ischemia, dementia, extrapyramidal syndrome, grand mal convulsion, hemiplegia, hypertonia, hypokinesia. Respiratory System:Frequent: pharyngitis, pneumonia, cough increased, bronchitis; Infrequent: dyspnea, rhinitis, asthma. Skin and Appendages:Frequent: rash, skin ulcer, pruritus; Infrequent: psoriasis, skin discoloration, herpes zoster, dry skin, sweating, urticaria, vesiculobullous rash. Special Senses:Infrequent: conjunctivitis, glaucoma, abnormal vision, ear pain, lacrimation disorder. Urogenital System:Frequent: urinary tract infection, cystitis, hematuria, glycosuria; Infrequent: vaginitis, dysuria, urinary frequency, albuminuria. ARICEPT 23mg/day Moderate to Severe Alzheimer's Disease ARICEPT 23mg/day has been administered to over 1300individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950patients have been treated for at least six months. The range of patient exposure was from 1 to over 500days. Adverse Events Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of ARICEPT 23mg/day due to adverse events was higher (18.6%) than for the 10mg/day treatment group (7.9%). The most common adverse events leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10mg/day are shown in Table5.
The majority of discontinuations due to adverse events in the 23mg group occurred during the first month of treatment. Most Frequent Adverse Events Seen in Association with the Use of 23mg The most common adverse events, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia. These adverse events were often of mild to moderate intensity. The events cited reflect experience gained under closely monitored conditions of a controlled clinical trial in a highly selected patient population. In actual clinical practice or in other clinical trials, these frequency estimates may not apply, as the conditions of use, reporting behavior, and the kinds of patients treated may differ. Table6 lists adverse events that were reported in at least 2% of patients who received 23mg/day of ARICEPT and at a higher frequency than those receiving 10mg/day of ARICEPT in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse events in patients taking ARICEPT with or without memantine.
Voluntary reports of adverse events temporally associated with ARICEPT that have been received since market introduction that are not listed above, and for which there are inadequate data to determine the causal relationship with the drug include the following: abdominal pain, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash. 7. DRUG INTERACTIONS 7.1. Effect of ARICEPT on the Metabolism of Other Drugs No invivo clinical trials have investigated the effect of ARICEPT on the clearance of drugs metabolized by CYP3A4 (e.g.cisapride, terfenadine) or by CYP2D6 (e.g.imipramine). However, invitro studies show a low rate of binding to these enzymes (mean Ki about 50-130μM), that, given the therapeutic plasma concentrations of donepezil (164nM), indicates little likelihood of interference. Whether ARICEPT has any potential for enzyme induction is not known. Formal pharmacokinetic studies eva luated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin, digoxin and ketoconazole. No effects of ARICEPT on the pharmacokinetics of these drugs were observed. 7.2. Effect of Other Drugs on the Metabolism of ARICEPT Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism invitro. Whether there is a clinical effect of quinidine is not known. In a 7-day crossover study in 18healthy volunteers, ketoconazole (200mg q.d.) increased mean donepezil (5mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown. A small effect of CYP2D6 inhibitors was identified in a population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease. Donepezil clearance was reduced by approximately 17% in patients taking 10 or 23mg in combination with a known CYP2D6 inhibitor. This result is consistent with the conclusion that CYP2D6 is a minor metabolic pathway of donepezil. Inducers of CYP2D6 and CYP3A4 (e.g.,phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of ARICEPT. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration of digoxin or cimetidine. 7.3. Use with Anticholinergics Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications. 7.4. Use with Cholinomimetics and Other Cholinesterase Inhibitors A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents or cholinergic agonists such as bethanechol. 8. USE IN SPECIFIC POPULATIONS 8.1. Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies in pregnant women. ARICEPT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16mg/kg/day (approximately 6times the maximum recommended human dose [MRHD] of 23mg/day on a mg/m2 basis) and 10mg/kg/day (approximately 7times the MRHD on a mg/m2 basis), respectively. Oral administration of donepezil (1, 3, 10mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day4 at the highest dose. The no-effect dose of 3mg/kg/day is approximately equal to the MRHD on a mg/m2 basis. 8.3. Nursing Mothers It is not known whether donepezil is excreted in human milk. Caution should be exercised when ARICEPT is administered to a nursing woman. 8.4. Pediatric Use The safety and effectiveness of ARICEPT in children have not been established. 8.5. Geriatric Use Alzheimer's disease is a disorder occurring primarily in individuals over 55years of age. The mean age of patients enrolled in the clinical studies with ARICEPT was 73years; 80% of these patients were between 65 and 84years 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 events reported by patient groups ≥65years old and <65years old. 8.6. Lower Weight Individuals In the controlled clinical trial, among patients in the ARICEPT 23mg treatment group, those patients weighing <55kg reported more nausea, vomiting, and decreased weight than patients weighing 55kg or more. There were more withdrawals due to adverse events as well. This finding may be related to higher plasma exposure associated with lower weight. 10. OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Tertiary anticholinergics such as atropine may be used as an antidote for ARICEPT overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0mg IV with subsequent doses based upon clinical response. Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate. It is not known whether ARICEPT and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration). Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation and lower body surface temperature. 11. DESCRIPTION ARICEPT (donepezil hydrochloride) is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-one hydrochloride. Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020. It has an empirical formula of C24H29NO3HCl and a molecular weight of 415.96. Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile and practically insoluble in ethyl acetate and in n-hexane.
ARICEPT is available for oral administration in film-coated tablets containing 5, 10, or 23mg of donepezil hydrochloride. Inactive ingredients in 5mg and 10mg tablets are lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate. The film coating contains talc, polyethylene glycol, hypromellose and titanium dioxide. Additionally, the 10mg tablet contains yellow iron oxide (synthetic) as a coloring agent. Inactive ingredients in 23mg tablets include ethylcellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate and methacrylic acid copolymer, TypeC. The film coating includes ferric oxide, hypromellose2910, polyethylene glycol8000, talc and titanium dioxide. ARICEPT ODT tablets are available for oral administration. Each ARICEPT ODT tablet contains 5 or 10mg of donepezil hydrochloride. Inactive ingredients are carrageenan, mannitol, colloidal silicon dioxide and polyvinyl alcohol. Additionally, the 10mg tablet contains ferric oxide (yellow) as a coloring agent. 12. CLINICAL PHARMACOLOGY 12.1. Mechanism of Action Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer's disease attribute some of them to a deficiency of cholinergic neurotransmission. Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase. There is no evidence that donepezil alters the course of the underlying dementing process. 12.2. Pharmacokinetics Pharmacokinetics of donepezil are linear over a dose range of 1-10mg given once daily. The rate and extent of absorption of ARICEPT tablets are not influenced by food. Based on population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease, following oral dosing, peak plasma concentration is achieved for ARICEPT 23mg tablets in approximately 8hours, compared with 3hours for ARICEPT 10mg tablets. Peak plasma concentrations were almost 2-fold higher for ARICEPT 23mg tablets than ARICEPT 10mg tablets. ARICEPT ODT 5mg and 10mg are bioequivalent to ARICEPT 5mg and 10mg tablets, respectively. A food effect study has not been conducted with ARICEPT ODT; however, the effect of food with ARICEPT ODT is expected to be minimal. ARICEPT ODT can be taken without regard to meals. The elimination half life of donepezil is about 70hours, and the mean apparent plasma clearance (Cl/F) is 0.13- 0.19L/hr/kg. Following multiple dose administration, donepezil accumulates in plasma by 4-7fold, and steady state is reached within 15days. The steady state volume of distribution is 12- 16L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1- acid glycoprotein (about 21%) over the concentration range of 2-1000ng/mL. Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil invitro and was found in plasma at concentrations equal to about 20% of donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10days, while 28% remained unrecovered, with about 17% of the donepezil dose recovered in the urine as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance. These results suggest CYP2D6 has a minor role in the metabolism of donepezil. Hepatic Disease: In a study of 10patients with stable alcoholic cirrhosis, the clearance of ARICEPT was decreased by 20% relative to 10healthy age- and sex-matched subjects. Renal Disease: In a study of 11patients with moderate to severe renal impairment (ClC <18mL/min/1.73m2) the clearance of ARICEPT did not differ from 11age- and sex-matched healthy subjects. Age: No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of ARICEPT. Population pharmacokinetic analysis suggested that the clearance of donepezil in patients decreases with increasing age. When compared with 65-year old, subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year old subjects have a 33% increase in clearance. The effect of age on donepezil clearance may not be clinically significant. Gender and Race: No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of ARICEPT. However, retrospective pharmacokinetic analysis and population pharmacokinetic analysis of plasma donepezil concentrations measured in patients with Alzheimer's disease indicates that gender and race (Japanese and Caucasians) did not affect the clearance of ARICEPT to an important degree. Body weight: There was a relationship noted between body weight and clearance. Over the range of body weight from 50kg to 110kg, clearance increased from 7.77L/h to 14.04L/h, with a value of 10L/hr for 70kg individuals. Drugs Highly Bound to Plasma Proteins: Drug displacement studies have been performed invitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. ARICEPT at concentrations of 0.3-10micrograms/mL did not affect the binding of furosemide (5micrograms/mL), digoxin (2ng/mL), and warfarin (3micrograms/mL) to human albumin. Similarly, the binding of ARICEPT to human albumin was not affected by furosemide, digoxin and warfarin. 13. NONCLINICAL TOXICOLOGY 13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil conducted in mice at oral doses up to 180mg/kg/day (approximately 40times the maximum recommended human dose [MRHD] of 23mg/day on a mg/m2 basis), or in a 104-week carcinogenicity study in rats at oral doses up to 30mg/kg/day (approximately 13times the MRHD on a mg/m2 basis). Donepezil was negative in a battery of genotoxicity assays (invitro bacterial reverse mutation, invitro mouse lymphoma tk, invitro chromosomal aberration, and invivo mouse micronucleus). Donepezil had no effect on fertility in rats at oral doses up to 10mg/kg/day (approximately 4times the MRHD on a mg/m2 basis) when administered to males and females prior to and during mating and continuing in females through implantation. 13.2. Animal Toxicology In a published study, female rats were given single doses of donepezil and memantine by intraperitoneal injection, each alone or in combination. When given in combination with memantine, donepezil increased the incidence and severity of memantine-induced neurodegeneration. The relevance of this finding to humans is unknown. 14. CLINICAL STUDIES The effectiveness of ARICEPT as a treatment for Alzheimer's disease is demonstrated by the results of randomized, double-blind, placebo-controlled clinical investigations. 14.1. Mild to Moderate Alzheimer's Disease The effectiveness of ARICEPT as a treatment for mild to moderate Alzheimer's disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer's disease (diagnosed by NINCDS and DSMIII-R criteria, Mini-Mental State Examination ≥10 and ≤26 and Clinical Dementia Rating of 1 or 2). The mean age of patients participating in ARICEPT trials was 73years with a range of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial distribution was white 95%, black 3% and other races 2%. Study Outcome Measures: In each study, the effectiveness of treatment with ARICEPT was eva luated using a dual outcome assessment strategy. The ability of ARICEPT to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer's disease patients. The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher. The patients recruited as participants in each study had mean scores on the ADAS-cog of approximately 26points, with a range from 4 to 61. Experience based on longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggest that scores on the ADAS-cog increase (worsen) by 6- 12points per year. However, smaller changes may be seen in patients with very mild or very advanced disease since the ADAS-cog is not uniformly sensitive to change over the course of the disease. The annualized rate of decline in the placebo patients participating in ARICEPT trials was approximately 2 to 4points per year. The ability of ARICEPT to produce an overall clinical effect was assessed using a Clinician's Interview-Based Impression of Change that required the use of caregiver information, the CIBIC-plus. The CIBIC-plus is not a single instrument and is not a standardized instrument like the ADAS-cog. Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure. As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-plus eva luations from other clinical trials. The CIBIC-plus used in ARICEPT trials was a semi-structured instrument that was intended to examine four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse." The CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods. Thirty-Week Study In a study of 30weeks duration, 473patients were randomized to receive single daily doses of placebo, 5mg/day or 10mg/day of ARICEPT. The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. The study was designed to compare 5mg/day or 10mg/day fixed doses of ARICEPT to placebo. However, to reduce the likelihood of cholinergic effects, the 10mg/day treatment was started following an initial 7-day treatment with 5mg/day doses. Effects on the ADAS-cog: Figure1 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 30weeks of the study. After 24weeks of treatment, the mean differences in the ADAS-cog change scores for ARICEPT treated patients compared to the patients on placebo were 2.8 and 3.1points for the 5mg/day and 10mg/day treatments, respectively. These differences were statistically significant. While the treatment effect size may appear to be slightly greater for the 10mg/day treatment, there was no statistically significant difference between the two active treatments. Following 6weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT treatment groups were indistinguishable from those patients who had received only placebo for 30weeks. This suggests that the beneficial effects of ARICEPT abate over 6weeks following discontinuation of treatment and do not represent a change in the underlying disease. There was no evidence of a rebound effect 6weeks after abrupt discontinuation of therapy.
Figure2 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained the measure of improvement in ADAS-cog score shown on the X axis. Three change scores, (7-point and 4-point reductions from baseline or no change in score) have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table. The curves demonstrate that both patients assigned to placebo and ARICEPT have a wide range of responses, but that the active treatment groups are more likely to show greater improvements. A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.
Effects on the CIBIC-plus: Figure3 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 24weeks of treatment. The mean drug-placebo differences for these groups of patients were 0.35points and 0.39points for 5mg/day and 10mg/day of ARICEPT, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments.
In a study of 15weeks duration, patients were randomized to receive single daily doses of placebo or either 5mg/day or 10mg/day of ARICEPT for 12weeks, followed by a 3-week placebo washout period. As in the 30-week study, to avoid acute cholinergic effects, the 10mg/day treatment followed an initial 7-day treatment with 5mg/day doses. Effects on the ADAS-Cog: Figure4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose groups over the 15weeks of the study. After 12weeks of treatment, the differences in mean ADAS-cog change scores for the ARICEPT treated patients compared to the patients on placebo were 2.7 and 3.0points each, for the 5 and 10mg/day ARICEPT treatment groups, respectively. These differences were statistically significant. The effect size for the 10mg/day group may appear to be slightly larger than that for 5mg/day. However, the differences between active treatments were not statistically significant.
Following 3weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT treatment groups increased, indicating that discontinuation of ARICEPT resulted in a loss of its treatment effect. The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but, the 30-week study (see above) demonstrated that treatment effects associated with the use of ARICEPT abate within 6weeks of treatment discontinuation. Figure5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the Xaxis. The same three change scores, (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration. The percentages of patients achieving those results are shown in the inset table. As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to ARICEPT have a wide range of responses, but that the ARICEPT treated patients are more likely to show greater improvements in cognitive performance.
Effects on the CIBIC-plus: Figure6 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 12weeks of treatment. The differences in mean scores for ARICEPT treated patients compared to the patients on placebo at Week12 were 0.36 and 0.38points for the 5mg/day and 10mg/day treatment groups, respectively. These differences were statistically significant.
In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT treatment. 14.2. Moderate to Severe Alzheimer's Disease The effectiveness of ARICEPT in the treatment of patients with moderate to severe Alzheimer's Disease was established in studies employing doses of 10 mg/day and 23 mg/day.
Swedish 6 Month Study The effectiveness of ARICEPT as a treatment for severe Alzheimer's disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (6month study) in patients with probable or possible Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Two hundred and forty eight (248) patients with severe Alzheimer's disease were randomized to ARICEPT or placebo. For patients randomized to ARICEPT, treatment was initiated at 5mg once daily for 28days and then increased to 10mg once daily. At the end of the 6month treatment period, 90.5% of the ARICEPT treated patients were receiving the 10mg/day dose. The mean age of patients was 84.9years, with a range of 59 to 99. Approximately 77% of patients were women, and 23% were men. Almost all patients were Caucasian. Probable AD was diagnosed in the majority of the patients (83.6% of ARICEPT treated patients and 84.2% of placebo treated patients). Study Outcome Measures: The effectiveness of treatment with ARICEPT was determined using a dual outcome assessment strategy that eva luated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on ARICEPT experienced significant improvement on both measures compared to placebo. The ability of ARICEPT to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the eva luation of cognitive function in patients with moderate to severe dementia. The SIB eva luates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment. Daily function was assessed using the Modified Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-severe). The ADCS-ADL-severe is derived from the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients. Each ADL item is rated from the highest level of independent performance to complete loss. The ADCS-ADL-severe is a subset of 19items, including ratings of the patient's ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment. The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient. Effects on the SIB: Figure7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 6months of the study. At 6months of treatment, the mean difference in the SIB change scores for ARICEPT treated patients compared to patients on placebo was 5.9points. ARICEPT treatment was statistically significantly superior to placebo.
Figure8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to ARICEPT and to placebo have a wide range of responses, the curves show that the ARICEPT group is more likely to show a greater improvement in cognitive performance.
Effects on the ADCS-ADL-severe: Figure9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 6months of the study. After 6months of treatment, the mean difference in the ADCS-ADL-severe change scores for ARICEPT treated patients compared to patients on placebo was 1.8points. ARICEPT treatment was statistically significantly superior to placebo. Figure10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores. While both patients assigned to ARICEPT and placebo have a wide range of responses, the curves demonstrate that the ARICEPT group is more likely to show a smaller decline or an improvement.
Japanese 24-Week Study In a study of 24weeks duration conducted in Japan, 325patients with severe Alzheimer's disease were randomized to doses of 5mg/day or 10mg/day of donepezil, administered once daily, or placebo. Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3mg/day, and extending over a maximum of 6weeks. Two hundred and forty eight (248) patients completed the study, with similar proportions of patients completing the study in each treatment group. The primary efficacy measures for this study were the SIB and CIBIC-plus. At 24weeks of treatment, statistically significant treatment differences were observed between the 10mg/day dose of donepezil and placebo on both the SIB and CIBIC-plus. The 5mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC-plus. Study of 23mg/day The effectiveness of ARICEPT 23mg/day as a treatment for moderate to severe Alzheimer's disease has been demonstrated by the results of a randomized, double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer's disease. The controlled clinical study was conducted globally in patients with probable Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0-20. Patients were required to have been on a stable dose of ARICEPT 10mg/day for at least 3months prior to screening. One thousand four hundred and thirty four (1434) patients with moderate to severe Alzheimer's disease were randomized to 23mg/day or 10mg/day. The mean age of patients was 73.8years, with a range of 47 to 90. Approximately 63% of patients were women, and 37% were men. Approximately 36% of the patients were taking memantine throughout the study. Study Outcome Measures: The effectiveness of treatment with 23mg/day was determined using a dual outcome assessment strategy that eva luated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment. This study showed that patients on 23mg/day experienced important clinical benefit on both measures compared to 10mg/day. The ability of 23mg/day to improve cognitive performance was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument, has been validated for the eva luation of cognitive function in patients with moderate to severe dementia. The SIB eva luates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction. The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment. The ability of 23mg/day to produce an overall clinical effect was assessed using a Clinician's Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines four major areas of patient function: General, Cognitive, Behavioral and Activities of Daily Living. It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating "markedly improved," to a score of 4, indicating "no change" to a score of 7, indicating "markedly worse." Effects on the SIB: Figure11 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24weeks of the study. At 24weeks of treatment, the LS mean difference in the SIB change scores for 23mg/day-treated patients compared to patients treated with 10mg was 2.2units (p= 0.0001). The dose of 23mg/day was statistically significantly superior to the dose of 10mg/day.
Figure12 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis. While patients assigned both to 23mg/day and to 10mg/day have a wide range of responses, the curves show that the 23mg-group is more likely to show a greater improvement in cognitive performance. When such curves are shifted to the left, this indicates a greater percentage of patients responding to treatment on the SIB.
Effects on the CIBIC-plus: Figure13 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the end of 24weeks of treatment. The mean difference between the 23mg/day and 10mg/day treatment groups was 0.06units. This difference was not statistically significant.
16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 ARICEPT Tablets Supplied as film-coated, round tablets containing 5mg, 10mg, or 23mg of donepezil hydrochloride. The 5mg tablets are white. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side. Bottles of 30 (NDC# 62856-245-30) The 10mg tablets are yellow. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side. Bottles of 30 (NDC# 62856-246-30) The 23mg tablets are reddish in color. The strength, in mg (23), is debossed on one side and ARICEPT is debossed on the other side. Bottles of 30 (NDC# 62856-247-30) 16.2. ARICEPT ODT Supplied as round tablets containing either 5mg or 10mg of donepezil hydrochloride. 5mg (White) Unit Dose Blister Package 30 (10x3) 10mg (Yellow) Unit Dose Blister Package 30 (10x3) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
ARICEPT(donepezil hydrochloride)tablets简介：
英文药名: ARICEPT(donepezil hydrochloride)tablets
中文药名: 盐酸多奈哌齐片
生产厂家: Eisai Inc.药品介绍：适应症 轻度或中度阿尔茨海默型痴呆症状的治疗用法用量 成年/老年人：初始治疗用量5mg ... 责任编辑：admin |
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