Cardiovascular conditions: Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes because of their pharmacological action. This effect may manifest as bradycardia or heart block in patients both with and without known underlying cardiac conduction abnormalities. Cases of syncopal episodes in association with the use of donepezil have also been reported.
Gastrointestinal conditions: Cholinesterase inhibitors may be expected to increase gastric acid secretion, through their primary action, due to increased cholinergic activity. Thus, patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, particularly those at increased risk for developing ulcers (e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs including high doses of acetylsalicylic acid).
However, clinical studies with donepezil have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
Donepezil hydrochloride has been shown to produce diarrhea, nausea and vomiting. These effects, when they occur, appear more frequently with the 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild and transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil. Treatment with the 5 mg/day dose for 4 to 6 weeks prior to increasing the dose to 10 mg/day is associated with a lower incidence of gastrointestinal intolerance.
Neurological conditions: Cholinomimetics are believed to have some potential to cause generalized convulsions. However, seizure activity may also be a manifestation of Alzheimer's disease.
There have been very rare post-marketing reports of neuroleptic malignant syndrome (NMS) in patients treated with donepezil with or without concomitant antipsychotic medication. NMS is a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, autonomic instability (e.g., irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia), altered consciousness and elevated serum creatine phosphokinase (CPK) levels. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever in the absence of additional clinical manifestations of NMS, donepezil therapy should be discontinued.
Mortality in subjects with vascular dementia: Three clinical trials of six months duration were conducted involving individuals meeting the National Institute of Neurological Disorders and Stroke (NINDS)-Association International pour la Recherche et l'Enseignement en Neurosciences (AIREN) for probable or possible vascular dementia (VaD) and excluding patients with a diagnosis of Alzheimer's disease. The mortality rate for the three VaD studied combined in the donepezil 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 donepezil 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 group relative to placebo.
When Alzheimer's disease studies were pooled, the mortality rate in the placebo group numerically exceeded that in the donepezil group. There is no evidence of an increased risk of mortality in the current approved indication of mild to moderately severe Alzheimer's disease.
Aggressive behavior: In patients with severe Alzheimer's disease, donepezil should be used with caution in patients with risk of aggression.
Rhabdomyolysis: Rare cases of rhabdomyolysis (including acute renal failure) have been reported in patients treated with donepezil, particularly in the days following dose initiation and dose increase. Majority of these cases occurred independently of the occurrence of NMS.
Patients should be carefully monitored for muscle pain, tenderness or weakness and darkened urine, particularly if accompanied by malaise or fever. Blood creatine phosphokinase levels should be assessed in patients experiencing these symptoms. Donepezil therapy should be discontinued if markedly elevated CPK levels are measured and/or if the patient develops signs and symptoms indicative of rhabdomyolysis. Although the decision to discontinue donepezil should be made based on the clinical judgment of the treating physician, in most postmarketing cases, therapy was withdrawn when CPK levels were 5X upper limit of normal or higher. Caution should be particularly exercised in prescribing donepezil to patients with predisposing/risk factors such as prior history of muscular disorders, uncontrolled hypothyroidism, hepatic or renal impairment, and in patients who are receiving concomitant medications that can cause rhabdomyolysis (e.g., statins, antipsychotics, selective serotonin reuptake inhibitor/serotonin norepinephrine reuptake inhibitor).
Genitourinary: Although not observed in clinical trials, cholinomimetics may cause bladder outflow obstruction.
Pulmonary conditions: Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease because of their cholinomimetic actions.
Anesthesia: Donepezil hydrochloride may exaggerate succinylcholine-type muscle relaxation during anesthesia.
Hepatic conditions: There is limited information regarding the pharmacokinetics of donepezil in hepatically impaired Alzheimer disease patients. Therefore, close monitoring for adverse effects in patients with hepatic disease being treated with donepezil is recommended.
Renal conditions: There is limited information regarding the pharmacokinetics of donepezil in renally impaired Alzheimer disease patients. Therefore, close monitoring for adverse effects in patients with renal disease being treated with donepezil is recommended.
Effects on Ability to Drive and Use Machine: Alzheimer's dementia may cause impairment of driving performance or compromise the ability to use machinery. In addition, donepezil can cause fatigue, dizziness, and muscle cramps, mainly when initiating or increasing the dose. The treating physician should routinely evaluate the ability of patients on donepezil to continue driving or operating complex machinery.
Use in Children: There are no adequate and well-controlled trails to document the safety and efficacy of donepezil in any illness occurring in children. Thus, donepezil is not recommended for use in children.
Use in Elderly: In Alzheimer's disease patients, nausea, diarrhea, vomiting, insomnia, fatigue, and anorexia increased with dose and age, and the incidence appeared to be greater in female patients. Since cholinesterase inhibitors as well as Alzheimer's disease can be associated with significant weight loss, caution is advised regarding the use of donepezil in low body weight elderly patients, particularly in those ≥85 years old.
There is limited safety information for donepezil in patients with mild to moderate or severe Alzheimer's disease and significant comorbidity. The use of donepezil in Alzheimer's disease patients with chronic illnesses common among the geriatric population, should be considered only after careful risk/benefit assessment and include close monitoring for adverse events. Caution is advised regarding the use of donepezil doses above 5 mg in this patient population. In severe Alzheimer's disease, the possibility of comorbid vascular disease and risk factors for vascular adverse events and mortality should be considered.