Donepezil Hydrochloride (Page 2 of 7)

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Donepezil hydrochloride has been administered to over 1,700 individuals during clinical trials worldwide. Approximately 1200 of these patients have been treated for at least 3 months and more than 1,000 patients have been treated for at least 6 months. Controlled and uncontrolled trials in the United States included approximately 900 patients. In regards to the highest dose of 10 mg/day, this population includes 650 patients treated for 3 months, 475 patients treated for 6 months, and 116 patients treated for over 1 year. The range of patient exposure is from 1 to 1,214 days.
Mild to Moderate Alzheimer’s Disease

Adverse Reactions Leading to Discontinuation
The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride tablets 5 mg/day treatment groups were comparable to those of placebo treatment groups at approximately 5%. The rate of discontinuation of patients who received 7-day escalations from 5 mg/day to 10 mg/day was higher at 13%.

The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice or more the incidence seen in placebo patients, are shown in Table 1.

Table 1. Most Common Adverse Reactions Leading to Discontinuation in Patients with Mild to Moderate Alzheimer’s Disease
Adverse Reaction Placebo (n=355) % 5 mg/day Donepezil Hydrochloride (n=350) % 10 mg/day Donepezil Hydrochloride (n=315) %
Nausea 1 1 3
Diarrhea 0 <1 3
Vomiting <1 <1 2

Most Common Adverse Reactions
The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving 10 mg/day and twice the placebo rate, are largely predicted by donepezil hydrochloride cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification.
There is evidence to suggest that the frequency of these common adverse reactions may be affected by the rate of titration. An open-label study was conducted with 269 patients who received placebo in the 15-and 30-week studies. These patients were titrated to a dose of 10 mg/day over a 6-week period. The rates of common adverse reactions were lower than those seen in patients titrated to 10 mg/day over one week in the controlled clinical trials and were comparable to those seen in patients on 5 mg/day. See Table 2 for a comparison of the most common adverse reactions following one and six week titration regimens.

Table 2. Comparison of Rates of Adverse Reactions in Mild to Moderate Patients Titrated to 10 mg/day over 1 and 6 Weeks
No titration One week titration Six week titration
Adverse Reaction Placebo (n=315) % 5 mg/day (n=311) % 10 mg/day (n=315) % 10 mg/day (n=269) %
Nausea 6 5 19 6
Diarrhea 5 8 15 9
Insomnia 6 6 14 6
Fatigue 3 4 8 3
Vomiting 3 3 8 5
Muscle cramps 2 6 8 3
Anorexia 2 3 7 3

Table 3 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received either donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age.

Table 3. Adverse Reactions in Pooled Placebo-Controlled Clinical Trials in Mild to Moderate Alzheimer’s Disease
Adverse Reaction Placebo (n=355) % Donepezil Hydrochloride (n=747) %
Percent of Patients with any Adverse Reaction 72 74
Nausea 6 11
Diarrhea 5 10
Headache 9 10
Insomnia 6 9
Pain, various locations 8 9
Dizziness 6 8
Accident 6 7
Muscle Cramps 2 6
Fatigue 3 5
Vomiting 3 5
Anorexia 2 4
Ecchymosis 3 4
Abnormal Dreams 0 3
Depression <1 3
Weight Loss 1 3
Arthritis 1 2
Frequent Urination 1 2
Somnolence <1 2
Syncope 1 2

Severe Alzheimer’s Disease (donepezil hydrochloride tablets 5 mg/day and 10 mg/day)

Donepezil hydrochloride has been administered to over 600 patients with severe Alzheimer’s disease during clinical trials of at least 6 months duration, including three double-blind, placebo-controlled trials, two of which had an open label extension.

Adverse Reactions Leading to Discontinuation

The rates of discontinuation from controlled clinical trials of donepezil hydrochloride due to adverse reactions for the donepezil hydrochloride patients were approximately 12% compared to 7% for placebo patients. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of donepezil hydrochloride patients and at twice or more the incidence seen in placebo, were anorexia (2% vs. 1% placebo), nausea (2% vs. <1% placebo), diarrhea (2% vs. 0% placebo), and urinary tract infection (2% vs. 1% placebo).

Most Common Adverse Reactions

The most common adverse reactions, defined as those occurring at a frequency of at least 5% in patients receiving donepezil hydrochloride and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride treatment without the need for dose modification.

Table 4 lists adverse reactions that occurred in at least 2% of patients in pooled placebo-controlled trials who received donepezil hydrochloride 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride than with placebo.

Table 4. Adverse Reactions in Pooled Controlled Clinical Trials in Severe Alzheimer’s Disease
Body System/Adverse Reaction Placebo (n=392) % Donepezil Hydrochloride (n=501) %
Percent of Patients with any Adverse Reaction 73 81
Accident 12 13
Infection 9 11
Diarrhea 4 10
Anorexia 4 8
Vomiting 4 8
Nausea 2 6
Insomnia 4 5
Ecchymosis 2 5
Headache 3 4
Hypertension 2 3
Pain 2 3
Back Pain 2 3
Eczema 2 3
Hallucinations 1 3
Hostility 2 3
Increase in Creatine Phosphokinase 1 3
Nervousness 2 3
Fever 1 2
Chest Pain <1 2
Confusion 1 2
Dehydration 1 2
Depression 1 2
Dizziness 1 2
Emotional Lability 1 2
Hemorrhage 1 2
Hyperlipemia <1 2
Personality Disorder 1 2
Somnolence 1 2
Syncope 1 2
Urinary Incontinence 1 2

Moderate to Severe Alzheimer’s Disease (Donepezil Hydrochloride Tablets 23 mg/day)
Donepezil hydrochloride tablets 23 mg/day have 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 Reactions Leading to Discontinuation The rate of discontinuation from a controlled clinical trial of donepezil hydrochloride tablets 23 mg/day due to adverse reactions was higher (19%) than for the 10 mg/day treatment group (8%). The most common adverse reactions leading to discontinuation, defined as those occurring in at least 1% of patients and greater than those occurring with 10 mg/day are shown in Table 5.

Table 5. Most Common Adverse Reactions Leading to Discontinuation in Patients with Moderate to Severe Alzheimer’s Disease
Adverse Reaction 23 mg/day Donepezil Hydrochlori de (n=963) % 10 mg/day Donepezil Hydrochloride (n=471) %
Vomiting 3 0
Diarrhea 2 0
Nausea 2 0
Dizziness 1 0

The majority of discontinuations due to adverse reactions in the 23 mg group occurred during the first month of treatment.

Most Common Adverse Reactions with Donepezil Hydrochloride Tablets 23 mg/day

The most common adverse reactions, defined as those occurring at a frequency of at least 5%, include nausea, diarrhea, vomiting, and anorexia.

Table 6 lists adverse reactions that occurred in at least 2% of patients who received 23 mg/day of donepezil hydrochloride and at a higher frequency than those receiving 10 mg/day of donepezil hydrochloride in a controlled clinical trial that compared the two doses. In this study, there were no important differences in the type of adverse reactions in patients taking donepezil hydrochloride with or without memantine.

Table 6. Adverse Reactions in a Controlled Clinical Trial in Moderate to Severe Alzheimer’s Disease
Adverse Reaction 23 mg/day Donepezil Hydrochloride (n=963) % 10 mg/day Donepezil Hydrochloride (n=471) %
Percent of Patients with any Adverse Reaction 74 64
Nausea 12 3
Vomiting 9 3
Diarrhea 8 5
Anorexia 5 2
Dizziness 5 3
Weight Loss 5 3
Headache 4 3
Insomnia 3 2
Urinary Incontinence 3 1
Asthenia 2 1
Contusion 2 0
Fatigue 2 1
Somnolence 2 1

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2024. All Rights Reserved.