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The approval of donepezil in several countries in America and Europe has been hailed as a major milestone, because it has met regulatory guidelines for the approval of anti-dementia drugs [ ]. Donepezil belongs to a piperidine class of reversible acetylcholinesterase inhibitors, chemically unrelated to either tacrine or physostigmine. It is highly specific for acetylcholinesterase and does not inhibit butyrylcholinesterase. The incidence of adverse effects with donepezil is comparable to that of placebo in controlled trials, and unlike tacrine, liver enzyme monitoring is not required. The long-term effectiveness of donepezil in large populations is yet to be established. Moreover, while it improves cognitive symptoms, it does not alter the course of the disease. Based on a limited number of studies, support for the use of donepezil in Alzheimer’s disease has emerged [ ].
Clinical trials of donepezil were funded by the manufacturer and appear to have been methodologically sound, although the absence of caregiver quality-of-life measures and outcomes related to activities of daily living is difficult to reconcile. An earlier 12-week study showed no improvement in caregiver quality of life with donepezil [ ]. As with most phase 3 studies, extrapolation of these results to routine practice is hampered by the fact that study populations are likely to be healthier than patients seen in routine clinical practice. Whether the results would be any different in a more heterogeneous population remains to be seen [ ].
In a more recent 12-week double-blind, placebo-controlled, parallel-group study, aimed at establishing the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer’s disease, donepezil (5 and 10 mg/day) was well tolerated and efficacious [ ]. Adverse events significantly more common with donepezil were nausea, insomnia, and diarrhea, which appeared to be dose related and did not require treatment. Seven patients treated with placebo and six in each of the donepezil groups had serious adverse events during the trial. Three had events that were considered possibly related to donepezil. These included gastric ulceration with hemorrhage, syncope and a transient ischemic attack, nausea, aphakia, tremor, and sweating. Both groups of patients treated with donepezil had falls in mean heart rate that were larger than with placebo. Two patients treated with donepezil had electrocardiographic changes: one developed an intraventricular conduction defect and ventricular extra beats, while the other had sinus arrhythmia, left axis deviation, and increased QRS voltage, possibly secondary to left ventricular enlargement. Neither reported cardiovascular adverse events. Two patients taking placebo also had electrocardiographic abnormalities: one with bundle branch block, the other with sinus bradycardia and ventricular extra beats.
The launch of donepezil has attracted intense interest among both the scientific community and the public. The debate regarding “lessons for health care policy” [ ] has been summarized:
Licensing trials in highly selected patients may provide insignificant information on which to base clinical decisions, especially when the effect sizes are small and comorbidity is common.
All trial evidence should be published before new drugs are marketed, and medical journals should not carry advertisements referring to unpublished data.
Communication of benefits and risks should emphasize clinical effect sizes rather than statistical significance.
Claims about effects on populations or services should be based on evidence.
Secrecy surrounding licensing should be ended, and data from trials should be available for independent analysis.
Overvaluation of new technology could threaten funding for vital but more mundane care.
There was intense debate in response to the above publication [ ].
Further evidence that donepezil is effective and well tolerated in treating symptoms of mild to moderately severe Alzheimer’s disease has emerged from a multinational trial [ ]. Common adverse effects were nausea, vomiting, diarrhea, anorexia, dizziness, and confusion, consistent with previous findings.
A meta-analysis of various drugs approved for treating Alzheimer’s disease in the USA and Canada has suggested that donepezil can delay cognitive impairment and deterioration in global health for at least 6 months in patients with mild-to-moderate Alzheimer’s disease [ ]. Patients taking active treatment will have more favorable Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) scores for at least 6 months, after which their scores will begin to converge with those who are taking placebo. The cost-effectiveness data were inconclusive.
Although once-daily donepezil is effective and well tolerated for the symptoms of mild-to-moderate Alzheimer’s disease [ ], two practical questions arise:
Which patients are too severely affected to be treated with donepezil?
At what point should donepezil be discontinued if the patient continues to deteriorate?
The current status of donepezil in the management of Alzheimer’s disease has been comprehensively reviewed [ ]. Several recent studies have confirmed the efficacy and tolerability of donepezil using different doses, study designs, and durations of treatment [ ]. Some relevant conclusions were the following:
Younger patients should be targeted for assessment and treatment [ ].
Of the patients 6% discontinued medication owing to adverse events [ ].
Sleep disturbances were more common in trials with bedtime dosing of donepezil [ ].
Long-term safety and realistic improvement were observed over a period of up to 4.9 years [ ].
The presence of the apolipoprotein E4 allele did not predict donepezil failure [ ].
Seven elderly patients with psychotic or non-psychotic behavioral symptoms in Lewy body dementia had some benefit from donepezil [ ]. Donepezil was withdrawn prematurely in three patients owing to poor response and/or adverse events. The adverse events were sedation, somnolence, worsening of chronic obstructive pulmonary disease, syncope, sweating, and bradycardia. These results have to be confirmed in controlled trials.
In two patients with Alzheimer’s disease, donepezil provided some benefit in relieving cognitive symptoms, but there were increased behavioral problems, such as anxiety, agitation, irritability, and lack of impulse control; these were then successfully controlled by adding gabapentin [ ].
Adverse reactions to donepezil in general practice have been evaluated in a post-marketing pharmacovigilance study in 1762 patients in the UK [ ]. This observational cohort study used the technique of prescription-event monitoring for a minimum period of 6 months. The commonest adverse events were nausea, diarrhea, malaise, dizziness, and insomnia. Aggression, agitation, and abnormal dreams were uncommonly associated with the drug. There were no causally associated cardiac rhythm disturbances or liver disorders. The authors suggested that the abnormal dreams and psychiatric disturbances were possible adverse drug reactions that require further confirmation.
The beneficial effect of donepezil on global ratings of dementia symptoms, cognition, and activities of daily living has been confirmed [ , ]. Donepezil was to be well tolerated for periods up to 1 year, and adverse events were usually mild and transient, lasted only an initial few days, and typically resolved without the need for dosage modification. It has been suggested that patients with Alzheimer’s disease do best while taking donepezil 10 mg/day and when the dosage is maintained at that level without interruption. Donepezil treatment effects that are lost after prolonged withdrawal do not fully recover when the drug is restarted [ ].
Symptomatic sinus bradycardia is a possible adverse effect of treatment with donepezil in Alzheimer’s disease [ ].
An 84-year-old patient with hypertensive cardiomyopathy developed bradycardia, fainting, and left-sided heart failure 3 weeks after starting treatment with donepezil. When donepezil was withdrawn, the sinus bradycardia disappeared; 24-hour electrocardiography showed no signs of sinus node disease, and no episodes of this type recurred during the next 6 months.
It is important to emphasize that disorders of cardiac rhythm associated with the use of donepezil are extremely unusual.
Convulsions have been reported during treatment with donepezil [ ].
A patient with mild Alzheimer’s disease taking donepezil, 5 mg/day for 2 weeks and then 10 mg/day for 23 days, was admitted with convulsions. His only other medication was aspirin 100 mg/day. Blood analysis was normal, and a computerized tomographic (CT) scan showed a mild degree of cortical atrophy with no structural lesions. Donepezil was withdrawn, and no other drug treatment was given. Six weeks later, donepezil 5 mg/day was restarted. On day 52, he developed loss of consciousness and convulsions, necessitating withdrawal of donepezil.
Convulsions in Alzheimer’s disease are very rare until late in the illness, and the authors attributed this patient’s convulsions to donepezil.
Restless legs, mumbling, and stuttering have been reported in a patient taking donepezil [ ]. According to the Naranjo probability scale, the causality was probable, since rechallenge was positive.
Extrapyramidal effects have been reported in three patients taking donepezil; in two cases, the effects disappeared when donepezil was withdrawn [ ].
Behavioral worsening in seven patients with Alzheimer’s disease after the start of donepezil therapy has been described [ ]. Their mean age was 76 years, and their mean score on the Mini-Mental State Examination was 18. Five patients had had dementia-related delusions and irritability before taking donepezil, one had had a history of major depression, and another had had a history of somatization disorder. At the start of treatment with donepezil, four were taking sertraline, one paroxetine, one venlafaxine, and four risperidone. All took donepezil 5 mg/day, and after 4–6 weeks the dosage in five patients was increased to 10 mg/day. In the other two cases, donepezil was discontinued after 5 weeks: in one case because of gastrointestinal symptoms and in the other because of increasing agitation. After an average of 7.3 (range 1–13) weeks after starting donepezil, all seven patients had a recurrence of previous behavioral problems. Five became agitated, one became depressed, and the other became more anxious and somatically preoccupied. The pattern of behavioral change involves regression to an earlier behavioral problem.
Violent behavior has been described with donepezil [ ].
A 76-year-old man who was taking oxybutynin 3 mg tds for bladder instability took donepezil 5 mg/day for presumed Alzheimer’s disease and 5 days later became very paranoid, believing that his wife had been stealing his money. He beat her and held her hostage in their house with a knife until their daughter intervened. He was given haloperidol 0.5 mg bd, and donepezil and oxybutynin were withdrawn. His paranoid ideation resolved within a few days and did not recur despite withdrawal of haloperidol.
Although a causal relation between this violent incident and donepezil cannot be proved, the temporal relation was suggestive.
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