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NEW ZEALAND DATA SHEET
1. PRODUCT NAME
Aricept 5 mg, 10 mg film coated tablet Aricept-D 5 mg, 10 mg orodispersible tablet
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
ARICEPT film-coated tablets for oral administration contain 5 mg or 10 mg donepezil hydrochloride equivalent to 4.56 mg or 9.12 mg donepezil free base, respectively. ARICEPT-D orally disintegrating tablets contain 5 mg or 10 mg donepezil hydrochloride equivalent to 4.56 mg or 9.12 mg donepezil free base, respectively. Excipient(s) with known effect ARICEPT film-coated tablets:
- Lactose monohydrate ARICEPT-D orally disintegrating tablets:
- Mannitol For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated and orally disintegrating tablets. ARICEPT 5 mg are white film-coated, round, embossed tablets, marked “ARICEPT” on one side and “5” on the other side. ARICEPT 10 mg are yellow film-coated, round, embossed tablets, marked “ARICEPT” on one side and “10” on the other side. ARICEPT-D 5 mg orally disintegrating tablets are white, round, embossed tablets, marked “ARICEPT” on one side and “5” on the other side. ARICEPT-D 10 mg orally disintegrating tablets are yellow, round, embossed tablets, marked “ARICEPT” on one side and “10” on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
ARICEPT is indicated for the treatment of mild, moderate and severe Alzheimer’s disease. ARICEPT is indicated for the treatment of vascular dementia (dementia associated with cerebrovascular disease).
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4.2 Dose and method of administration
Dose Adults/Elderly Treatment should be initiated and supervised by a doctor experienced in the diagnosis and treatment of Alzheimer’s Dementia. Individual response to donepezil cannot be predicted. Treatment should be continued for as long as a therapeutic benefit for the patient exists. Discontinuation of therapy should be considered where there is no longer evidence of a therapeutic effect, which should be assessed by periodic evaluations by the physician using input from the patient and caregiver. The use of donepezil in patients with other types of dementia or other types of memory impairment (e.g., age-related cognitive decline), has not been established. The dosages of ARICEPT shown to be effective in controlled clinical trials are 5 mg and 10 mg administered once daily. Although there is no statistically significant evidence that a greater treatment effect is obtained from the use of the 10 mg dose, there is a suggestion, based on analysis of group data that some additional benefits may accrue to some patients from the use of the higher dose. Treatment is initiated at 5 mg/day (once-a-day dosing). ARICEPT film-coated tablets and ARICEPT-D orally disintegrating tablets should be taken orally, in the evening, just prior to retiring. ARICEPT-D orally disintegrating tablets should be placed on the tongue and allowed to disintegrate before swallowing with or without water, according to patient preference. Both formulations can be taken with or without food The 5 mg/day dose should be maintained for at least one month in order to allow the earliest clinical responses to treatment to be assessed and to allow steady-state concentrations of donepezil to be achieved. Following a one-month clinical assessment of treatment at 5 mg/day, the dose of ARICEPT can be increased to 10 mg/day (once-a-day dosing). The maximum recommended daily dose is 10 mg. Upon discontinuation of treatment, a gradual abatement of the beneficial effects of ARICEPT is seen. There is no evidence of a rebound effect after abrupt discontinuation of therapy. Renal and Hepatic Impairment A similar dose schedule can be followed for patients with renal or mild to moderate hepatic impairment as clearance of donepezil is not significantly affected by these conditions. Paediatric Population Donepezil hydrochloride is not recommended for use in children (see section 4.4, Paediatric population).
4.3 Contraindications
ARICEPT is contraindicated in patients with a known hypersensitivity to donepezil hydrochloride, piperidine derivatives, or to any excipients used in the formulation.
Version: pfdarict 10519 Superseded: pfdarict If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, treatment should be discontinued immediately. 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. The administration of donepezil hydrochloride concomitantly with other inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system should be avoided. Mortality in Subjects with Vascular Dementia Three clinical trials of 6 months duration were conducted studying individuals meeting the NINDS-AIREN criteria for probable or possible vascular dementia (VaD) and excluding patients with a diagnosis of Alzheimer’s disease. In the first study, the mortality rates were 2/198 (1.0%) on ARICEPT 5 mg, 5/206 (2.4%) on ARICEPT 10 mg and 7/199 (3.5%) on placebo. In the second study, the mortality rates were 4/208 (1.9%) on ARICEPT 5 mg, 3/215 (1.4%) on ARICEPT 10 mg and 1/193 (0.5%) on placebo. In the third study, the mortality rates were 11/648 (1.7%) on ARICEPT 5 mg and 0/326 (0%) on placebo (p<0.02). The mortality rate for the three VaD studies combined in the ARICEPT group (1.7%) was numerically higher than in the placebo group (1.1%); however, this difference was not statistically significant. The majority of deaths in patients taking either ARICEPT or placebo appear to result from various vascular related causes, which could be expected in this elderly population with underlying vascular disease. An analysis of all serious non-fatal and fatal vascular events showed no difference in the rate of occurrence in the donepezil hydrochloride group relative to placebo. When Alzheimer’s disease studies were pooled (n=4146), the mortality rate in the placebo group numerically exceeded that in the ARICEPT group. There is no evidence of an increased risk of mortality in the current approved indications of mild, moderate and severe Alzheimer’s disease. Paediatric Population ARICEPT is not recommended for use in children.
4.5 Interaction with other medicines and other forms of interaction
The administration of donepezil hydrochloride concomitantly with other cholinesterase inhibitors should be avoided. Drugs Highly Bound to Plasma Proteins Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as frusemide, digoxin, and warfarin. ARICEPT at concentrations of 0.3-10 μg/mL did not affect the binding of frusemide (5 μg/mL), digoxin (2 ng/mL) and warfarin (3 μg/mL) to human albumin. Similarly, the binding of ARICEPT to human albumin was not affected by frusemide, digoxin and warfarin.
Version: pfdarict 10519 Superseded: pfdarict Effect of ARICEPT on the Metabolism of Other Drugs No in vivo clinical trials have investigated the effect of ARICEPT on the clearance of drugs metabolised by CYP 3A4 (e.g. cisapride, terfenadine) or by CYP 2D6 (e.g. imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean K i about 50 - 130 μM), that, given the therapeutic plasma concentrations of donepezil (164 nM), indicates little likelihood of interference. Whether ARICEPT has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of ARICEPT for interaction with theophylline, cimetidine, warfarin and digoxin. No significant effects on the pharmacokinetics of these drugs were observed. Donepezil hydrochloride and/or any of its metabolites does not inhibit the metabolism of thioridazine, risperidone or sertraline in humans. In a study of Parkinson’s disease patients on optimal treatment with L-dopa/carbidopa, administration of donepezil hydrochloride for 21 days had no effect on L-dopa or carbidopa blood levels. In this study, no effects on motor activity were observed. Effect of Other Drugs on the Metabolism of ARICEPT In vitro studies have shown that the cytochrome P450 isoenzymes 3A4 and to a minor extent 2D6 are involved in the metabolism of donepezil. Ketoconazole and quinidine, inhibitors of CYP450, 3A4 and 2D6, respectively, inhibit donepezil metabolism in vitro. Therefore these and other CYP3A4 inhibitors, such as itraconazole and erythromycin, and CYP2D inhibitors, such as fluoxetine could inhibit the metabolism of donepezil. Whether there is a clinical effect of these inhibitors is not known. In two studies in healthy volunteers, ketoconazole increased mean donepezil concentrations by about 30%. These increases are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway and are not likely to be clinically relevant. Administration of donepezil had no effect on the pharmacokinetics of ketoconazole. Inducers of CYP 2D6 and CYP 3A4 (e.g., phenytoin, carbamazepine, dexamethasone, rifampicin, phenobarbital and alcohol) could increase the rate of elimination of ARICEPT. Since the magnitude of an inhibiting or inducing effect is unknown, such drug combinations should be used with care. Formal pharmacokinetic studies demonstrated that the metabolism of ARICEPT is not significantly affected by concurrent administration of digoxin, cimetidine, thioridazine, risperidone or sertraline. Donepezil hydrochloride has the potential to interfere with medications having anticholinergic activity. There is also the potential for synergistic activity with concomitant treatment involving such medications as succinylcholine, other neuro-muscular blocking agents or cholinergic agonists or beta blocking agents which have effects on cardiac conduction, but an in vitro study showed that donepezil hydrochloride had minimal effects on hydrolysis of succinylcholine.
Version: pfdarict 10519 Superseded: pfdarict Adverse Events Leading to Discontinuation In trials of mild to moderate Alzheimer's disease, the rate of discontinuation for the ARICEPT 5 mg/day treatment group was comparable to that of placebo-treated patients at approximately 5%. The rate of discontinuation of patients who received rapid dose escalations over 7 days from 5 mg/day to 10 mg/day, was higher at 13%. The most common signs and symptoms leading to discontinuation were nausea, diarrhoea and vomiting. For patients who did not discontinue, these signs and symptoms generally proved to be mild and transient, resolving in 1 to 2 days during continued use of the 10 mg/day dose. There is evidence to suggest that the frequency of these common adverse events may be affected by the rate of titration. Adverse Events listed below were derived from the 15- and 30-week studies (see section 5.1) and a pivotal study of 14 weeks duration.
Version: pfdarict 10519 Superseded: pfdarict Table 1: Adverse Events Reported in Controlled Clinical Trials in at Least 2% of Patients Receiving ARICEPT and at a Higher Frequency than Placebo-treated Patients System Organ Class/Adverse Event Placebo (n=355) Donepezil (n=747) Percent of Patients with any Adverse Event 72% 74% Blood and Lymphatic System Disorders Ecchymosis 3% 4% Metabolism and Nutrition Disorders Weight Decrease 1% 3% Nervous System Disorders Insomnia 6% 9% Dizziness 6% 8% Depression <1% 3% Abnormal Dreams 0% 3% Somnolence <1% 2% Cardiac Disorders Syncope 1% 2% Gastrointestinal Disorders Nausea 6% 11% Diarrhoea 5% 10% Vomiting 3% 5% Anorexia 2% 4% Musculoskeletal and Connective Tissue Disorders Muscle Cramps 2% 6% Arthritis 1% 2% Renal and Urinary Disorders Frequent Urination 1% 2% General Disorders and Administration Site Conditions Headache 9% 10% Pain, various locations 8% 9% Accident 6% 7% Fatigue 3% 5% Other Adverse Events Observed During Clinical Trials Treatment emergent signs and symptoms that occurred during three controlled clinical trials were recorded as adverse events by the clinical investigators using terminology of their own choosing. All adverse events occurring at least twice and judged as possibly or definitely related to ARICEPT treatment are included, except for those already listed in Table 1. Events are classified by body system and include frequent adverse events - those occurring in at least 1/100 patients; infrequent adverse events - those occurring in 1/100 to 1/1000 patients. Metabolism and Nutrition Disorders : dehydration, oedema of extremities Nervous System Disorders : agitation, anxiety, confusion, delusions, hallucinations, tremor, irritability, aggression, vertigo, ataxia, increased libido, restlessness, abnormal crying, aphasia, coldness (localised), muscle spasm, hypokinesia, nervousness, paraesthesia, paranoia, wandering
Version: pfdarict 10519 Superseded: pfdarict syndrome and pancreatitis. However, there is inadequate data to determine the causal relationship with ARICEPT. Reporting of Suspected Adverse Reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions https://nzphvc.otago.ac.nz/reporting/.
4.9 Overdose
Animal Study Data The estimated median lethal dose of donepezil hydrochloride following administration of a single oral dose in mice, rats and dogs is 45, 32 and 15 mg/kg, respectively, or approximately 225, 160 and 75 times the maximum recommended human dose of 10 mg per day. Dose-related signs of cholinergic stimulation were observed in animals and included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, fasciculation and lower body surface temperature. Cholinergic Crisis Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterised 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. Treatment As in any case of overdosage, general supportive measures should be utilised. Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride overdosage. Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg 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 donepezil hydrochloride and/or its metabolites can be removed by dialysis (haemodialysis, peritoneal dialysis, or haemofiltration). For advice on the management of overdose please contact the National Poisons Centre on 0800 POISON (0800 764766).
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ARICEPT (donepezil hydrochloride) is a specific and reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (RS)- 1 - benzyl- 4 - [5,6-dimethoxy- 1 - indanon)- 2 - yl]
- methylpiperidine hydrochloride. The CAS reference number for donepezil hydrochloride is 120011 - 70 - 3. Donepezil hydrochloride has an empirical formula of C 24 H 29 NO 3 HCl and a molecular weight of 415.96.
Version: pfdarict 10519 Superseded: pfdarict 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. Mechanism of Action It has been demonstrated that Alzheimer's disease is associated with a relative decrease in the activity of the cholinergic system in the cerebral cortex and other areas of the brain. Studies suggest that donepezil hydrochloride exerts its therapeutic effect by enhancing cholinergic function in the central nervous system. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of acetylcholinesterase. Donepezil hydrochloride is a specific and reversible inhibitor of acetylcholinesterase, the predominant cholinesterase in the brain. Donepezil hydrochloride was found in vitro to be over 1000 times more potent an inhibitor of this enzyme than of butyrylcholinesterase, an enzyme which is present mainly outside the central nervous system. Alzheimer’s Disease In patients with Alzheimer’s dementia participating in clinical trials, administration of single daily doses of 5 mg or 10 mg of donepezil hydrochloride produced steady-state inhibition of acetylcholinesterase activity (measured in erythrocyte membranes) of 63.6% and 77.3%, respectively when measured post dose. The inhibition of acetylcholinesterase (AChE) in red blood cells by donepezil hydrochloride has been shown to correspond closely to the effects in the cerebral cortex. In addition, significant correlation was demonstrated between plasma levels of donepezil hydrochloride, AChE inhibition and change in ADAS-cog, a sensitive and well validated scale which examines cognitive performance - including memory, orientation, attention, reason, language and praxis. Clinical Efficacy and Safety Mild to Moderately Severe Alzheimer's disease Studies of Less Than One Year Duration The effectiveness of ARICEPT in the treatment of Alzheimer's disease has been demonstrated by two randomised, double-blind, placebo-controlled studies (15- and 30-week) in which 436 patients were treated with ARICEPT. Criteria for inclusion were patients with mild to moderately severe Alzheimer's disease (diagnosed by NINCDS and DSM III-R criteria, Mini- Mental State Examination 10 and 26 and Clinical Dementia Rating of 1 or 2). Study Outcome Measures : In each study, the effectiveness of treatment with ARICEPT was evaluated 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.
Version: pfdarict 10519 Superseded: pfdarict Figure 1. Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing 24 Weeks of Treatment. Figure 2 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 this 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, respectively. 0 6 12 18 24 30 4 3 2 1 0
- Clinical Decline Placebo 5 mg/day 10 mg/day Clinical Improvement Mean ( + SE) Change from Baseline ADAS-cog Rating Weeks of Drug Treatment Placebo
Version: pfdarict 10519 Superseded: pfdarict Figure 2. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with Specified Changes from Baseline ADAS-cog Scores. The Percentages of Randomized Patients who Completed the Study were: Placebo 80%, 5 mg/day 85% and 10 mg/day 68%. Effects on the CIBIC plus: Figure 3 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment. The mean drug-placebo differences for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10 mg/day of ARICEPT, respectively. These differences were statistically significant. There was no statistically significant difference between the two active treatments. Figure 3. Frequency Distribution of CIBIC plus Scores at Week 24 0 20 40 60 80 100 120 -15 -10 -5 0 5 10 15 Cumulative Percentage of Patients Change from Baseline Placebo Aricept 5mg Aricept 10mg Change in ADAS-cog Treatment Group - 7 - 4 0 Placebo 8% 28% 59% 5 mg/day 15% 40% 83% 10 mg/day 26% 58% 82% 7 points 4 points no change 0 10 20 30 40 50 Placebo 5 mg/day 10 mg/day CIBIC plus Rating Markedly Improved Moderately Improved Minimally Improved No Change Minimally Worse Moderately Worse Markedly Worse Percentage of Patients
Version: pfdarict 10219 Superseded: pfdarict 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 the greater improvements in cognitive performance. Figure 5. Cumulative Percentage of Patients with Specified Changes from Baseline ADAS-cog Scores. The Percentages of Randomized Patients Within Each Treatment Group Who Completed the Study Were: Placebo 93%, 5 mg/day 90% and 10 mg/day 82 %. Effects on the CIBIC plus: Figure 6 is a histogram of the frequency distribution of CIBIC plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment. The differences in mean scores for ARICEPT treated patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 units for the 5 mg/day and 10 mg/day treatment groups, respectively. These differences were statistically significant.
Version: pfdarict 10219 Superseded: pfdarict Figure 6. Frequency Distribution of CIBIC plus Scores at Week 12 In both studies, patient age, sex and race were not found to predict the clinical outcome of ARICEPT treatment. Studies of Greater Than One Year Duration The effectiveness of ARICEPT in the treatment of Alzheimer's disease has been demonstrated by two randomised, double-blind, placebo-controlled studies (54-week) in which 356 patients were treated with ARICEPT. Fifty Four-Week Study # In a 54-week double-blinded study, patients were randomised to receive either placebo or 5 mg ARICEPT once daily for 28 days followed by 10 mg once daily for the remainder of the study. Criteria for inclusion included: diagnosis of mild to moderate Alzheimer’s disease (DSM-IV, 290.00 or 290.10 of the NINCDS criteria), Clinical Dementia Rating (CDR)=1 or 2, MMSE of 12 - 20, retention of at least 8 Instrumental Activities of Daily Living (IADLs) and at least 5 basic Activities of Daily Living (ADLs) and a modified Hachinski score 4. The intent to treat analysis consisted of 207 ARICEPT-treated patients and 208 placebo patients. Study outcome measure: The primary outcome measure for assessment of efficacy of ARICEPT was based upon attrition from the study due to clinically evident functional decline. Patients were assessed at 6-week intervals. Attrition was determined by the investigator as follows: 1) a clinically significant decline in ability to perform one or more basic ADL which were present at baseline, 2) a clinically significant decline in ability to perform 20% or more of IADLs which were present at baseline, or 3) an increase in CDR score compared to baseline. Basic ADL items are defined by the patient’s ability in toileting, feeding, dressing, personal hygiene/grooming, bathing and walking. Instrumental ADLs involve the assessment of 10 items: use of telephone, household tasks, using household appliances, managing money, shopping, food preparations, ability to get around inside and outside home, hobbies and 0 10 20 30 40 50 CIBIC plus Rating Markedly Improved Moderately Improved Minimally Improved No Change Minimally Worse Moderately Worse Markedly Worse Placebo 5 mg/day 10 mg/day Percentage of Patients
Version: pfdarict 10219 Superseded: pfdarict treat analysis of observed cases, ARICEPT-treated patients performed significantly better than placebo patients at 24, 36 and 52 weeks. Figure 8. LS Mean Change from Baseline for GBS Total Score by Week and Treatment Group – ITT population (Observed Cases and Week 52 LOCF) Quality of Life Although a trend of improvement on quality of life (QOL) measures was observed in clinical trials of ARICEPT treated patients, there were large variances in QOL scores. These are consistent with observations regarding quality of life assessments in Alzheimer's disease patients generally. It has been demonstrated that Alzheimer's disease patients' opinions will be influenced by the day-to-day fluctuations in their illness (often quite substantial), leading to similar day-to-day variability in their perception of quality of life. Alzheimer's disease patients may also be unreliable sources of information on quality of life because of significant losses in executive functions such as judgement, memory, and insight that are key to obtaining meaningful assessments. Severe Alzheimer's Disease Studies of Less than One Year Duration The effectiveness of ARICEPT in the treatment of severe Alzheimer's disease has been demonstrated by three randomised, double-blind, placebo-controlled studies (one 26 week and two 24 week) in which 517 patients were randomised to receive ARICEPT. Criteria for inclusion were patients with severe Alzheimer's disease (diagnosed by NINCDS-ADRDA and DSM IV criteria, Mini-Mental State Examination (MMSE) and a Functional Assessment Staging (FASt). Study Outcome Measures : In each study, the effectiveness of treatment with ARICEPT was evaluated using a combination of assessments of cognition, global function, activities of daily living (daily function), and behavioural and psychological symptoms. Cognition
Version: pfdarict 10219 Superseded: pfdarict SIB : The primary tool in the three studies used to assess cognition was the Severe Impairment Battery (SIB). The SIB evaluates cognitive dysfunction over nine domains (social interactions, memory, orientation, language, attention, praxis, visuospatial, construction and orienting to name). Total scores range from 1 to 100, and lower scores indicate greater impairment. MMSE : Cognitive changes over time are often assessed using the Mini-Mental State Examination (MMSE), a 30 point test. Lower scores indicate a greater degree of impairment, and scores <12 points or <10 points have been used to define the severe stages of dementia. The MMSE was used in 2 of the studies as a secondary endpoint. Global Function CIBIC plus: Similar to the studies in mild to moderate Alzheimer's disease, the Clinician's Interview Based Impression of Change with caregiver input (CIBIC plus) was used as a primary endpoint to assess global function for two of the three studies. CGI-I: In one of the studies, the Clinical Global Impression of Improvement (CGI-I) was used as a primary endpoint as a measure of global function. Similar to CIBIC plus, the physician rates the patient's condition relative to baseline on a 7-point Likert-like scale, with scores of 1-3 representing degrees of improvement, 4 representing no change, and 5- 7 representing degrees of worsening. Activities of Daily Living ADCS-ADL-severe: To assess activities of daily living (ADL), all three studies used the modified ADCS-ADL inventory for severe Alzheimer's disease (ADCS-ADL-severe). This is based on an interview with the caregiver and measures the patient's most usual and consistent ability to perform basic and instrumental ADL during the previous 4 weeks. The scale ranges from 0 to 54, with lower scores indicating greater functional impairment. Behavioural and Psychological Symptoms Two scales were used to assess behavioural and psychological symptoms: the neuropsychiatric inventory (NPI) and the Behavioural Pathology in Alzheimer's disease scale (BEHAVE-AD). NPI: The 12 item NPI, used in 2 studies, is based on the caregiver's assessment of the frequency and severity of a range of mood and behavioural disturbances since the last evaluation. Total NPI scores range from 0 (best score) to 144 (worst score). BEHAVE-AD: The BEHAVE-AD scale, used in 1 study, is similarly based on the caregiver's assessment of the presence and magnitude of a range of neuropsychiatric symptoms over the past two weeks. Total BEHAVE-AD scores range from 0 (best score) to 78 (worst score). Twenty-Six-Week Study In a study of 26 weeks duration, safety and efficacy were evaluated by randomising 249 patients to receive a single daily dose of placebo or 10 mg/day of ARICEPT. To reduce the likelihood of cholinergic effects, treatment was initiated at 5 mg/day for 4 weeks, then treatment was increased to 10 mg/day, based on clinical judgement. At any time during the study, the dose of donepezil could be reduced from 10 mg to 5 mg daily based on the
