CONTRAINDICATIONS
Donepezil HCl is contraindicated in patients with known hypersensitivity to donepezil HCl or to
piperidine derivatives.
WARNINGS
Anesthesia
Donepezil HCl, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle
relaxation during anesthesia.
Cardiovascular Conditions
Because of their pharmacological action, cholinesterase inhibitors may have vagotonic effects on
heart rate (e.g., bradycardia). The potential for this action may be particularly important to patients
with "sick sinus syndrome" or other supraventricular cardiac conduction conditions. Syncopal
episodes have been reported in association with the use of donepezil HCl.
Gastrointestinal Conditions
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 antiinflammatory drugs (NSAIDS)). Clinical studies of donepezil HCl have shown no
increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal
bleeding.
Donepezil HCl, 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 10 mg/day dose than with the 5 mg/day dose. In most cases, these effects have been mild
and transient, sometimes lasting 1-3 weeks, and have resolved during continued use of donepezil
HCl.
Genitourinary
Although not observed in clinical trials of donepezil HCl, cholinomimetics may cause bladder
outflow obstruction.
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.
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.
PRECAUTIONS
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies of donepezil have not been completed.
Donepezil was not mutagenic in the Ames reverse mutation assay in bacteria. In the chromosome
aberration test in cultures of Chinese hamster lung (CHL) cells, some clastogenic effects were
observed. Donepezil was not clastogenic in the in vivo mouse micronucleus test.
Donepezil had no effect on fertility in rats at doses of up to 10 mg/kg/day (approximately 8 times
the maximum recommended human dose (MRHD) on a mg/m2 basis).
Pregnancy Category C
Teratology studies conducted in pregnant rats at doses of up to 16 mg/kg/day (approximately 13
times the MRHD on a mg/m2 basis) and in pregnant rabbits at doses of up to 10 mg/kg/day
(approximately 16 times the MRHD on a mg/m2 basis) did not disclose any evidence for a
teratogenic potential of donepezil. However, in a study in which pregnant rats were given up to 10
mg/kg/day (approximately 8 times the MRHD on a mg/m2 basis) from day 17 of gestation through
day 20 postpartum, there was a slight increase in stillbirths and a slight decrease in pup survival
through day 4 postpartum at this dose; the next lower dose tested was 3 mg/kg/day. There are no
adequate or well-controlled studies in pregnant women. Donepezil HCl should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether donepezil is excreted in human breast milk. Donepezil HCl has no indication
for use in nursing mothers.
Pediatric Use
There are no adequate and well-controlled trials to document the safety and efficacy of donepezil
HCl in any illness occurring in children.