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warnings and cautions
5 WARNINGS AND PRECAUTIONS A dose of ARICEPT 23 should not be administered until patients have been on a daily dose of 10 mg donepezil hydrochloride for 4 to 6 weeks ( 5.1 ). Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block ( 5.3 ). Patients should be monitored closely for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers ( 5.4 ). ARICEPT 23 is associated with weight loss. Consideration should be given when prescribing ARICEPT 23 to patients of lower weight ( 5.5 ). 5.1 Initiation of Treatment Because donepezil steady state is achieved about 15 days after dosing is started, and because the incidence of untoward effects may be influenced by the rate of dose escalation, a dose of ARICEPT 23 should not be administered until patients have been on a daily dose of 10 mg donepezil hydrochloride for 4 to 6 weeks. 5.2 Anesthesia ARICEPT 23, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. 5.3 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 23. 5.4 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 anti-inflammatory drugs (NSAIDS). Results of a controlled clinical study of ARICEPT 23 showed an increase relative to donepezil hydrochloride 10 mg/day, in the incidence of peptic ulcer disease (0.4% vs. 0.2%) and gastrointestinal bleeding from any site (1.1% vs. 0.6%). ARICEPT 23 has been shown to produce diarrhea, nausea and vomiting as a result of its pharmacological properties. In most cases, these effects have been mild to moderate and transient, sometimes lasting one to three weeks, and have resolved during continued use of ARICEPT 23. 5.5 Weight Loss Weight loss was reported as an adverse event in 4.7% of patients assigned to ARICEPT 23 compared to 2.5% of patients assigned to 10 mg donepezil hydrochloride. Compared to their baseline weights, 8.4% of patients in the ARICEPT 23 group were found to have a weight decrease of ≥ 7% by the end of the study, while 4.9% of the group taking 10 mg donepezil hydrochloride was found to have weight loss. Therefore, consideration should be given when prescribing ARICEPT 23 to patients of lower weight. 5.6 Genitourinary Although not observed in clinical trials of ARICEPT 23, 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 The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients with moderate to severe Alzheimer's disease receiving 23 mg/day of ARICEPT 23 are nausea, diarrhea, vomiting, and anorexia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-888-274-2378 (fax 1-201-746-3207) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience ARICEPT 23 has been administered to over 1300 individuals globally in clinical trials. Approximately 1050 of these patients have been treated for at least three months and more than 950 patients have been treated for at least six months. The range of patient exposure was from 1 to over 500 days. Adverse Events Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of ARICEPT 23 due to adverse events was higher (18.6%) than for the donepezil 10 mg/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 donepezil 10 mg/day doses, are shown in Table 1. Table 1. Most Frequent Adverse Events Leading to Withdrawal from a Controlled Clinical Trial by Treatment Group Dose Group ARICEPT 23 mg/day Donepezil 10 mg/day Safety Population 963 471 Event/ %Discontinuing Diarrhea 2.9 0.4 Nausea 1.9 0.4 Vomiting 1.7 0.4 Dizziness 1.1 0.0 The majority of discontinuations due to adverse events in the ARICEPT 23 group occurred during the first month of treatment. Most Frequent Adverse Clinical Events Seen in Association with the Use of ARICEPT 23 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 and transient, resolving during continued ARICEPT 23 treatment. Adverse Events Reported in Controlled Trials 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. Table 2 lists treatment emergent signs and symptoms that were reported in at least 2% of patients in a controlled trial who received ARICEPT 23 or 10 mg donepezil hydrochloride. Table 2. Adverse Events Reported in a Controlled Clinical Trial in Moderate to Severe Alzheimer's Disease in at Least 2% of Patients Body System/Adverse Event ARICEPT 23 mg/day Donepezil 10 mg/day Safety Population 963 471 Percent of Patients with any Adverse Event 73.7 63.7 Gastrointestinal disorders Nausea 11.8 3.4 Vomiting 9.2 2.5 Diarrhea 8.3 5.3 General disorders and administration site conditions Fatigue 2.4 0.8 Asthenia 2.1 0.6 Infections and infestations Urinary tract infection 4.4 4.0 Nasopharyngitis 2.9 3.4 Injury, poisoning and procedural complications Fall 4.0 3.8 Contusion 2.1 0.2 Investigations Weight decreased 4.7 2.5 Metabolism and nutrition disorders Anorexia 5.3 1.7 Nervous system Dizziness 4.9 3.4 Headache 4.3 3.2 Somnolence 2.1 1.1 Psychiatric disorders Agitation 3.9 3.8 Anxiety 1.3 2.5 Insomnia 3.4 2.3 Aggression 2.7 2.5 Renal and urinary disorders Urinary incontinence 2.5 1.3 Vascular disorders Hypertension 1.9 3.4 6.2 Postmarketing Experience with 5 and 10 mg Donepezil Hydrochloride Tablets The following adverse reactions have been identified during post approval use of donepezil hydrochloride 5 and 10 mg tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include the following: abdominal pain, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.