Donepezil ER Tablets
Name: Donepezil ER Tablets
- Donepezil ER Tablets 10 mg
- Donepezil ER Tablets tablet
- Donepezil ER Tablets drug
- Donepezil ER Tablets action
- Donepezil ER Tablets 180 mg
- Donepezil ER Tablets oral dose
Adverse Reactions
The following serious adverse reactions are described below and elsewhere in the labeling:
- Cardiovascular Conditions [see Warnings and Precautions ( 5.2)]
- Nausea and Vomiting [see Warnings and Precautions ( 5.3)]
- Peptic Ulcer Disease and GI Bleeding [see Warnings and Precautions ( 5.4)]
- Weight Loss [see Warnings and Precautions ( 5.5)]
- Genitourinary Conditions [see Warnings and Precautions ( 5.6)]
- Neurological Conditions: Seizures [see Warnings and Precautions ( 5.7)]
- Pulmonary Conditions [see Warnings and Precautions ( 5.8)]
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 tablets have 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 tablets 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.
| Adverse Reaction | Placebo (n=355) % | 5 mg/day (n=350) % | 10 mg/day (n=315) % |
| Nausea | 1 | 1 | 3 |
| Diarrhea | 0 | <1 | 3 |
| Vomiting | <1 | <1 | 2 |
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 tablets’ cholinomimetic effects. These include nausea, diarrhea, insomnia, vomiting, muscle cramp, fatigue, and anorexia. These adverse reactions were often transient, resolving during continued donepezil hydrochloride tablets 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.
| No titration | One week titration | Six week titration | ||
| Adverse Reaction | Placebo | 5 mg/day | 10 mg/day | 10 mg/day |
| 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 tablets 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride tablets than with placebo. In general, adverse reactions occurred more frequently in female patients and with advancing age.
| Adverse Reaction | Placebo | Donepezil Hydrochloride Tablets |
| 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 tablets have 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 tablets due to adverse reactions for the donepezil hydrochloride tablets 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 tablets 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 tablets and at twice or more the placebo rate, are largely predicted by donepezil hydrochloride tablets’ cholinomimetic effects. These include diarrhea, anorexia, vomiting, nausea, and ecchymosis. These adverse reactions were often transient, resolving during continued donepezil hydrochloride tablets 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 tablets 5 mg or 10 mg and for which the rate of occurrence was greater for patients treated with donepezil hydrochloride tablets than with placebo.
| Body System/Adverse Reaction | Placebo | Donepezil Hydrochloride Tablets |
| 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.
| Adverse Reaction | 23 mg/day (n=963) % | 10 mg/day (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 tablets and at a higher frequency than those receiving 10 mg/day of donepezil hydrochloride tablets 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 tablets with or without memantine.
| Adverse Reaction | 23 mg/day (n=963) % | 10 mg/day (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 |
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use donepezil hydrochloride 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.
Abdominal pain, agitation, aggression, cholecystitis, confusion, convulsions, hallucinations, heart block (all types), hemolytic anemia, hepatitis, hyponatremia, neuoleptic malignant syndrome, pancreatitis, rash, rhabdomyolysis, QTc prolongation, and torsade de pointes.
Drug Interactions
7.1 Use with Anticholinergics
Because of their mechanism of action, cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications.
7.2 Use with Cholinomimetics and Other Cholinesterase Inhibitors
A synergistic effect may be expected when cholinesterase inhibitors are given concurrently with succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists such as bethanechol.
Nonclinical Toxicology
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was obtained in an 88-week carcinogenicity study of donepezil conducted in mice at oral doses up to 180 mg/kg/day (approximately 40 times the maximum recommended human dose [MRHD] of 23 mg/day on a mg/m 2 basis), or in a 104-week carcinogenicity study in rats at oral doses up to 30 mg/kg/day (approximately 13 times the MRHD on a mg/m 2 basis).
Donepezil was negative in a battery of genotoxicity assays ( in vitro bacterial reverse mutation, in vitro mouse lymphoma tk, in vitro chromosomal aberration, and in vivo mouse micronucleus).
Donepezil had no effect on fertility in rats at oral doses up to 10 mg/kg/day (approximately 4 times the MRHD on a mg/m 2 basis) when administered to males and females prior to and during mating and continuing in females through implantation.
13.2 Animal Toxicology and/or Pharmacology
In an acute dose neurotoxicity study in female rats, oral administration of donepezil and memantine in combination resulted in increased incidence, severity, and distribution of neurodegeneration compared with memantine alone. The no-effect levels of the combination were associated with clinically relevant plasma donepezil and memantine levels.
The relevance of this finding to humans is unknown.
Package label
| DONEPEZIL HYDROCHLORIDE donepezil hydrochloride tablet, extended release | ||||||||||||||||||||||||||||||||
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| Labeler - TWi Pharmaceuticals, Inc. (658402052) |
| Registrant - TWi Pharmaceuticals, Inc. (658402052) |
| Establishment | |||
| Name | Address | ID/FEI | Operations |
| TWi Pharmaceuticals, Inc. Zhongli Plant | 658863394 | manufacture(24979-004), analysis(24979-004), pack(24979-004) | |