| Undesirable effects | Clinical Studies Experience |
Undesirable effects
The most common adverse events are diarrhea, muscle cramps, fatigue, nausea, vomiting and insomnia. The incidence profile for adverse events for severe Alzheimer’s disease is similar to that of mild to moderately severe Alzheimer’s disease. The table below reflects the incidence of adverse events in patients receiving treatment with Donepezil hydrochloride (ARICEPT®) for all stages of Alzheimer’s disease.
Adverse reactions reported as more than an isolated case are listed below, by system organ class and by frequency. Frequencies are defined as: very common (≥ 1/10), common (≥1/100, <1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,100), very rare (<1/10,000) and not known (cannot be estimated from available data).
| System Organ Class | Very common | Common | Uncommon | Rare |
| Infections and infestations | Common cold | |||
| Metabolism and nutrition disorder | Anorexia | |||
| Psychiatric disorders | Hallucinations**, Agitation**, Aggressive behavior** | |||
| Nervous system disorder | Syncope*, Dizziness, Insomnia | Seizure* | Extrapyramidal symptoms | |
| Cardiac disorder | Bradycardia | Sino-atrial block Atrioventricular block | ||
| Gastrointestinal disorder | Diarrhea, Nausea | Vomiting, Abdominal disturbance | Gastrointestinal hemorrhage, Gastric and Duodenal ulcers | |
| Hepato-biliary disorders | Liver dysfunction including hepatitis*** | |||
| Skin and subcutaneous tissue disorder | Rash, Puritus | |||
| Musculoskeletal connective tissue disorders | Muscle cramps | |||
| Renal and urinary disorders | Urinary Incontinence | |||
| General disorders and administration site conditions | Headache | Fatigue, Pain | ||
| Investigations | Minor increase in serum concentration of muscle creatinine kinase | |||
| Injury and poisoning | Accident |
* In investigating patients for syncope or seizure, the possibility of heart block or long sinusal pauses should be considered. ** Reports of hallucinations, agitation, aggressive behavior have resolved on dose-reduction or discontinuation of treatment. *** In cases of unexplained liver dysfunction, withdrawal of Donepezil hydrochloride (ARICEPT®) should be considered.
Clinical Studies Experience
Donepezil hydrochloride (ARICEPT®) 23 mg tablets 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 Donepezil hydrochloride (ARICEPT®) 23 mg tablets 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 Discontinuation from a Controlled Clinical Trial by Treatment Group | ||
| Dose Group | 23 mg/day ARICEPT | 10 mg/day ARICEPT |
| Safety Population | 963 | 471 |
| Event/ % Discontinuing | ||
| Vomiting | 3 | 0 |
| Diarrhea | 2 | 0 |
| Nausea | 2 | 0 |
| Dizziness | 1 | 0 |
The majority of discontinuations due to adverse events in the Donepezil hydrochloride (ARICEPT®) 23 mg tablets group occurred during the first month of treatment.
Most Frequent Adverse Clinical Events Seen in Association with the Use of Donepezil hydrochloride (ARICEPT®) 23 mg tablets
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.
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 adverse events that were reported in at least 2% of patients who received 23 mg/day of Donepezil hydrochloride (ARICEPT®) and at a higher frequency than those receiving 10 mg/day of Donepezil hydrochloride (ARICEPT®) in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse events in patients taking Donepezil hydrochloride (ARICEPT®) with or without memantine.
| Table 2. Adverse Events Reported in a Controlled Clinical Trial in Moderate to Severe Alzheimer’s Disease in at Least 2% of Patients and Higher in the 23 mg/day Group | ||
| Body System/Adverse Event | 23 mg/day ARICEPT | 10 mg/day ARICEPT |
| Safety Population | 963 | 471 |
| Percent of Patients with any Adverse Event | 74 | 64 |
| Gastrointestinal disorders | ||
| Nausea | 12 | 3 |
| Vomiting | 9 | 3 |
| Diarrhea | 8 | 5 |
| General disorders and administration site conditions | ||
| Fatigue | 2 | 1 |
| Asthenia | 2 | 1 |
| Injury, poisoning and procedural complications | ||
| Contusion | 2 | 0 |
| Investigations | ||
| Weight decreased | 5 | 3 |
| Metabolism and nutrition disorders | ||
| Anorexia | 5 | 2 |
| Nervous system | ||
| Dizziness | 5 | 3 |
| Headache | 4 | 3 |
| Somnolence | 2 | 1 |
| Psychiatric disorders | ||
| Insomnia | 3 | 2 |
| Renal and urinary disorders | ||
| Urinary incontinence | 3 | 1 |
Post-marketing Experience with 5 mg and 10 mg Donepezil Hydrochloride (ARICEPT®) 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, agitation, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuroleptic malignant syndrome, pancreatitis, and rash.
| Reporting of suspected adverse drug reactions |
| Please contact: |
| HI-Eisai Pharmaceutical, Inc. |
| +63 2 88875837 / +63 2 88875160 / +63 9088672236 |
| Or Report to FDA Philippines: www.fda.gov.ph |