Donepezil hydrochloride 5 MG Oral Tablet
Generic Name: DONEPEZIL HYDROCHLORIDE
Brand Name: donepezil hydrochloride
- Substance Name(s):
- DONEPEZIL HYDROCHLORIDE
DRUG INTERACTIONS
7 • Cholinesterase inhibitors have the potential to interfere with the activity of anticholinergic medications ( 7.1 ).
• A synergistic effect may be expected with concomitant administration of succinylcholine, similar neuromuscular blocking agents, or cholinergic agonists ( 7.2 ).
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.
OVERDOSAGE
10 Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug.
As in any case of overdose, general supportive measures should be utilized.
Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse, and convulsions.
Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved.
Tertiary anticholinergics such as atropine may be used as an antidote for donepezil hydrochloride overdosage.
Intravenous atropine sulfate titrated to effect is recommended: an initial dose of 1.0 to 2.0 mg IV with subsequent doses based upon clinical response.
Atypical responses in blood pressure and heart rate have been reported with other cholinomimetics when co-administered with quaternary anticholinergics such as glycopyrrolate.
It is not known whether donepezil hydrochloride and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis, or hemofiltration).
Dose-related signs of toxicity in animals included reduced spontaneous movement, prone position, staggering gait, lacrimation, clonic convulsions, depressed respiration, salivation, miosis, tremors, fasciculation, and lower body surface temperature.
DESCRIPTION
11 Donepezil hydrochloride is a reversible inhibitor of the enzyme acetylcholinesterase, known chemically as (±)-2, 3-dihydro-5, 6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1 H -inden-1-one hydrochloride.
Donepezil hydrochloride is commonly referred to in the pharmacological literature as E2020.
It has an empirical formula of C 24 H 29 NO 3 HCl and a molecular weight of 415.96.
Donepezil hydrochloride is a white crystalline powder and is freely soluble in chloroform, soluble in water and in glacial acetic acid, slightly soluble in ethanol and in acetonitrile, and practically insoluble in ethyl acetate and in n-hexane.
Donepezil Hydrochloride Tablets, USP, are available for oral administration in film-coated tablets containing 5 or 10 mg of donepezil hydrochloride.
Inactive ingredients in 5 mg and 10 mg tablets are lactose monohydrate, hydroxypropyl cellulose, magnesium Stearate, microcrystalline cellulose, corn starch, Croscarmellose sodium.
Additionally, the 5 mg tablets coating film contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, and FD&C blue.
The 10 mg tablets coating film contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, iron oxide yellow and iron oxide red.
Structural Formula
CLINICAL STUDIES
14 14.1 Mild to Moderate Alzheimer’s Disease The effectiveness of donepezil hydrochloride as a treatment for mild to moderate Alzheimer’s disease is demonstrated by the results of two randomized, double-blind, placebo-controlled clinical investigations in patients with Alzheimer’s disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination ≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2).
The mean age of patients participating in donepezil hydrochloride trials was 73 years with a range of 50 to 94.
Approximately 62% of patients were women and 38% were men.
The racial distribution was white 95%, black 3%, and other races 2%.
The higher dose of 10 mg did not provide a statistically significantly greater clinical benefit than 5 mg.
There is a suggestion, however, based upon order of group mean scores and dose trend analyses of data from these clinical trials, that a daily dose of 10 mg of donepezil hydrochloride might provide additional benefit for some patients.
Accordingly, whether or not to employ a dose of 10 mg is a matter of prescriber and patient preference.
Study Outcome Measures In each study, the effectiveness of treatment with donepezil hydrochloride was evaluated using a dual outcome assessment strategy.
The ability of donepezil hydrochloride to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s disease patients.
The ADAS-cog examines selected aspects of cognitive performance including elements of memory, orientation, attention, reasoning, language, and praxis.
The ADAS-cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment.
Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.
The patients recruited as participants in each study had mean scores on the ADAS-cog of approximately 26 points, with a range from 4 to 61.
Experience based on longitudinal studies of ambulatory patients with mild to moderate Alzheimer’s disease suggest that scores on the ADAS-cog increase (worsen) by 6-12 points per year.
However, smaller changes may be seen in patients with very mild or very advanced disease since the ADAS-cog is not uniformly sensitive to change over the course of the disease.
The annualized rate of decline in the placebo patients participating in donepezil hydrochloride trials was approximately 2 to 4 points per year.
The ability of donepezil hydrochloride to produce an overall clinical effect was assessed using a Clinician’s Interview-Based Impression of Change that required the use of caregiver information, the CIBIC-plus.
The CIBIC-plus is not a single instrument and is not a standardized instrument like the ADAS-cog.
Clinical trials for investigational drugs have used a variety of CIBIC formats, each different in terms of depth and structure.
As such, results from a CIBIC-plus reflect clinical experience from the trial or trials in which it was used and cannot be compared directly with the results of CIBIC-plus evaluations from other clinical trials.
The CIBIC-plus used in donepezil hydrochloride trials was a semi-structured instrument that was intended to examine four major areas of patient function: General, Cognitive, Behavioral, and Activities of Daily Living.
It represents the assessment of a skilled clinician based upon his/her observations at an interview with the patient, in combination with information supplied by a caregiver familiar with the behavior of the patient over the interval rated.
The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change” to a score of 7, indicating “markedly worse.” The CIBIC-plus has not been systematically compared directly to assessments not using information from caregivers (CIBIC) or other global methods.
Thirty-Week Study In a study of 30 weeks duration, 473 patients were randomized to receive single daily doses of placebo, 5 mg/day or 10 mg/day of donepezil hydrochloride.
The 30-week study was divided into a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period.
The study was designed to compare 5 mg/day or 10 mg/day fixed doses of donepezil hydrochloride to placebo.
However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment was started following an initial 7-day treatment with 5 mg/day doses.
Effects on the ADAS-cog Figure 1 illustrates the time course for the change from baseline in ADAS-cog scores for all three dose groups over the 30 weeks of the study.
After 24 weeks of treatment, the mean differences in the ADAS-cog change scores for donepezil hydrochloride treated patients compared to the patients on placebo were 2.8 and 3.1 points for the 5 mg/day and 10 mg/day treatments, respectively.
These differences were statistically significant.
While the treatment effect size may appear to be slightly greater for the 10 mg/day treatment, there was no statistically significant difference between the two active treatments.
Following 6 weeks of placebo washout, scores on the ADAS-cog for both the donepezil hydrochloride treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks.
This suggests that the beneficial effects of donepezil hydrochloride abate over 6 weeks following discontinuation of treatment and do not represent a change in the underlying disease.
There was no evidence of a rebound effect 6 weeks after abrupt discontinuation of therapy.
Figure 1.
Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing 24 Weeks of Treatment Figure 2 illustrates the cumulative percentages of patients from each of the three treatment groups who had attained the measure of improvement in ADAS-cog score shown on the X axis.
Three change scores (7-point and 4-point reductions from baseline or no change in score) have been identified for illustrative purposes, and the percent of patients in each group achieving that result is shown in the inset table.
The curves demonstrate that both patients assigned to placebo and donepezil hydrochloride have a wide range of responses, but that the active treatment groups are more likely to show greater improvements.
A curve for an effective treatment would be shifted to the left of the curve for placebo, while an ineffective or deleterious treatment would be superimposed upon or shifted to the right of the curve for placebo.
Figure 2.
Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with Specified Changes from Baseline ADAS-cog Scores.
The Percentages of Randomized Patients who Completed the Study were: Placebo 80%, 5 mg/day 85%, and 10 mg/day 68%.
Figure 1 Figure 2 Effects on the CIBIC-plus Figure 3 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 24 weeks of treatment.
The mean drug-placebo differences for these groups of patients were 0.35 points and 0.39 points for 5 mg/day and 10 mg/day of donepezil hydrochloride, respectively.
These differences were statistically significant.
There was no statistically significant difference between the two active treatments.
Figure 3.
Frequency Distribution of CIBIC-plus Scores at Week 24.
Fifteen-Week Study In a study of 15 weeks duration, patients were randomized to receive single daily doses of placebo or either 5 mg/day or 10 mg/day of donepezil hydrochloride for 12 weeks, followed by a 3-week placebo washout period.
As in the 30-week study, to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial 7-day treatment with 5 mg/day doses.
Figure 3 Effects on the ADAS-cog Figure 4 illustrates the time course of the change from baseline in ADAS-cog scores for all three dose groups over the 15 weeks of the study.
After 12 weeks of treatment, the differences in mean ADAS-cog change scores for the donepezil hydrochloride treated patients compared to the patients on placebo were 2.7 and 3.0 points each, for the 5 and 10 mg/day donepezil hydrochloride treatment groups, respectively.
These differences were statistically significant.
The effect size for the 10 mg/day group may appear to be slightly larger than that for 5 mg/day.
However, the differences between active treatments were not statistically significant.
Figure 4.
Time-course of the Change from Baseline in ADAS-cog Score for Patients Completing the 15-week Study.
Following 3 weeks of placebo washout, scores on the ADAS-cog for both the donepezil hydrochloride treatment groups increased, indicating that discontinuation of donepezil hydrochloride resulted in a loss of its treatment effect.
The duration of this placebo washout period was not sufficient to characterize the rate of loss of the treatment effect, but the 30-week study (see above) demonstrated that treatment effects associated with the use of donepezil hydrochloride abate within 6 weeks of treatment discontinuation.
Figure 5 illustrates the cumulative percentages of patients from each of the three treatment groups who attained the measure of improvement in ADAS-cog score shown on the X axis.
The same three change scores (7-point and 4-point reductions from baseline or no change in score) as selected for the 30-week study have been used for this illustration.
The percentages of patients achieving those results are shown in the inset table.
As observed in the 30-week study, the curves demonstrate that patients assigned to either placebo or to donepezil hydrochloride have a wide range of responses, but that the donepezil hydrochloride treated patients are more likely to show greater improvements in cognitive performance.
Figure 5.
Cumulative Percentage of Patients with Specified Changes from Baseline ADAS-cog Scores.
The Percentages of Randomized Patients Within Each Treatment Group Who Completed the Study Were: Placebo 93%, 5 mg/day 90%, and 10 mg/day 82%.
Figure 4 Figure 5 Effects on the CIBIC-plus Figure 6 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients assigned to each of the three treatment groups who completed 12 weeks of treatment.
The differences in mean scores for donepezil hydrochloride treated patients compared to the patients on placebo at Week 12 were 0.36 and 0.38 points for the 5 mg/day and 10 mg/day treatment groups, respectively.
These differences were statistically significant.
Figure 6.
Frequency Distribution of CIBIC-plus Scores at Week 12.
In both studies, patient age, sex and race were not found to predict the clinical outcome of donepezil hydrochloride treatment.
Figure 6 14.2 Moderate to Severe Alzheimer’s Disease The effectiveness of donepezil hydrochloride in the treatment of patients with moderate to severe Alzheimer’s disease was established in studies employing doses of 10 mg/day.
Swedish 6 Month Study (10 mg/day) The effectiveness of donepezil hydrochloride as a treatment for severe Alzheimer’s disease is demonstrated by the results of a randomized, double-blind, placebo-controlled clinical study conducted in Sweden (6 month study) in patients with probable or possible Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10.
Two hundred and forty eight (248) patients with severe Alzheimer’s disease were randomized to donepezil hydrochloride or placebo.
For patients randomized to donepezil hydrochloride, treatment was initiated at 5 mg once daily for 28 days and then increased to 10 mg once daily.
At the end of the 6 month treatment period, 90.5% of the donepezil hydrochloride treated patients were receiving the 10 mg/day dose.
The mean age of patients was 84.9 years, with a range of 59 to 99.
Approximately 77 % of patients were women, and 23 % were men.
Almost all patients were Caucasian.
Probable Alzheimer’s disease was diagnosed in the majority of the patients (83.6% of donepezil hydrochloride treated patients and 84.2% of placebo treated patients).
Study Outcome Measures The effectiveness of treatment with donepezil hydrochloride was determined using a dual outcome assessment strategy that evaluated cognitive function using an instrument designed for more impaired patients and overall function through caregiver-rated assessment.
This study showed that patients on donepezil hydrochloride experienced significant improvement on both measures compared to placebo.
The ability of donepezil hydrochloride to improve cognitive performance was assessed with the Severe Impairment Battery (SIB).
The SIB, a multi-item instrument, has been validated for the evaluation of cognitive function in patients with moderate to severe dementia.
The SIB evaluates selective aspects of cognitive performance, including elements of memory, language, orientation, attention, praxis, visuospatial ability, construction, and social interaction.
The SIB scoring range is from 0 to 100, with lower scores indicating greater cognitive impairment.
Daily function was assessed using the Modified Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory for Severe Alzheimer’s Disease (ADCS-ADL-severe).
The ADCS-ADL-severe is derived from the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions used to measure the functional capabilities of patients.
Each ADL item is rated from the highest level of independent performance to complete loss.
The ADCS-ADL-severe is a subset of 19 items, including ratings of the patient’s ability to eat, dress, bathe, use the telephone, get around (or travel), and perform other activities of daily living; it has been validated for the assessment of patients with moderate to severe dementia.
The ADCS-ADL-severe has a scoring range of 0 to 54, with the lower scores indicating greater functional impairment.
The investigator performs the inventory by interviewing a caregiver, in this study a nurse staff member, familiar with the functioning of the patient.
Effects on the SIB Figure 7 shows the time course for the change from baseline in SIB score for the two treatment groups over the 6 months of the study.
At 6 months of treatment, the mean difference in the SIB change scores for donepezil hydrochloride treated patients compared to patients on placebo was 5.9 points.
Donepezil hydrochloride treatment was statistically significantly superior to placebo.
Figure 7.
Time Course of the Change from Baseline in SIB Score for Patients Completing 6 Months of Treatment.
Figure 8 illustrates the cumulative percentages of patients from each of the two treatment groups who attained the measure of improvement in SIB score shown on the X-axis.
While patients assigned both to donepezil hydrochloride and to placebo have a wide range of responses, the curves show that the donepezil hydrochloride group is more likely to show a greater improvement in cognitive performance.
Figure 8.
Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with Particular Changes from Baseline in SIB Scores.
Figure 9.
Time Course of the Change from Baseline in ADCS-ADL-Severe Score for Patients Completing 6 Months of Treatment.
Figure 7 Figure 8 Figure 9 Effects on the ADCS-ADL-severe Figure 9 illustrates the time course for the change from baseline in ADCS-ADL-severe scores for patients in the two treatment groups over the 6 months of the study.
After 6 months of treatment, the mean difference in the ADCS-ADL-severe change scores for donepezil hydrochloride treated patients compared to patients on placebo was 1.8 points.
Donepezil hydrochloride treatment was statistically significantly superior to placebo.
Figure 10 shows the cumulative percentages of patients from each treatment group with specified changes from baseline ADCS-ADL-severe scores.
While both patients assigned to donepezil hydrochloride and placebo have a wide range of responses, the curves demonstrate that the donepezil hydrochloride group is more likely to show a smaller decline or an improvement.
Figure 10.
Cumulative Percentage of Patients Completing 6 Months of Double-blind Treatment with Particular Changes from Baseline in ADCS-ADL-Severe Scores.
Figure 10 Japanese 24-Week Study (10 mg/day) In a study of 24 weeks duration conducted in Japan, 325 patients with severe Alzheimer’s disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered once daily, or placebo.
Patients randomized to treatment with donepezil were to achieve their assigned doses by titration, beginning at 3 mg/day, and extending over a maximum of 6 weeks.
Two hundred and forty eight (248) patients completed the study, with similar proportions of patients completing the study in each treatment group.
The primary efficacy measures for this study were the SIB and CIBIC-plus.
At 24 weeks of treatment, statistically significant treatment differences were observed between the 10 mg/day dose of donepezil and placebo on both the SIB and CIBIC-plus.
The 5 mg/day dose of donepezil showed a statistically significant superiority to placebo on the SIB, but not on the CIBIC-plus.
HOW SUPPLIED
16 /STORAGE AND HANDLING 16.1 Donepezil Hydrochloride Tablets Supplied as film-coated, round tablets containing 5 mg, or 10 mg of donepezil hydrochloride, USP.
The 5 mg tablets are blue, round, film-coated tablets, debossed with ‘HH205′ on one side.
• Bottles of 30 (NDC# 43547-275-03) • Bottles of 90 (NDC# 43547-275-09) • Bottles of 1000 (NDC# 43547-275-11) The 10 mg tablets are light yellow, round, film-coated tablets, debossed with ‘HH210′ on one side.
• Bottles of 30 (NDC# 43547-276-03) • Bottles of 90 (NDC# 43547-276-09) • Bottles of 1000 (NDC# 43547-276-11) Storage Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).
GERIATRIC USE
8.5 Geriatric Use Alzheimer’s disease is a disorder occurring primarily in individuals over 55 years of age.
The mean age of patients enrolled in the clinical studies with donepezil hydrochloride was 73 years; 80% of these patients were between 65 and 84 years old, and 49% of patients were at or above the age of 75.
The efficacy and safety data presented in the clinical trials section were obtained from these patients.
There were no clinically significant differences in most adverse reactions reported by patient groups ≥ 65 years old and < 65 years old.
DOSAGE FORMS AND STRENGTHS
3 Donepezil hydrochloride is supplied as film-coated, round tablets containing 5 mg, 10 mg of donepezil hydrochloride, USP.
The 5 mg tablets are blue, round, film-coated tablets, debossed with ‘HH205′ on one side.
The 10 mg tablets are light yellow, round, film-coated tablets, debossed with ‘HH210’ on one side.
Tablets: 5 mg, 10 mg ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action Current theories on the pathogenesis of the cognitive signs and symptoms of Alzheimer’s disease attribute some of them to a deficiency of cholinergic neurotransmission.
Donepezil hydrochloride is postulated to exert its therapeutic effect by enhancing cholinergic function.
This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase.
There is no evidence that donepezil alters the course of the underlying dementing process.
INDICATIONS AND USAGE
1 Donepezil hydrochloride is indicated for the treatment of dementia of the Alzheimer’s type.
Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.
Donepezil hydrochloride is an acetylcholinesterase inhibitor indicated for the treatment of dementia of the Alzheimer’s type.
Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s Disease ( 1 ).
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of donepezil hydrochloride in pregnant women.
In animal studies, developmental toxicity was not observed when donepezil was administered to pregnant rats and rabbits during organogenesis, but administration to rats during the latter part of pregnancy and throughout lactation resulted in increased stillbirths and decreased offspring survival at clinically relevant doses [see Data].
In the U.S.
general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.
The background risks of major birth defects and miscarriage for the indicated population are unknown.
Data Animal Data Oral administration of donepezil to pregnant rats and rabbits during the period of organogenesis did not produce any teratogenic effects at doses up to 16 mg/kg/day (approximately 16 times the maximum recommended human dose [MRHD] of 10 mg/day on a mg/m 2 basis) and 10 mg/kg/day (approximately 20 times the MRHD on a mg/m 2 basis), respectively.
Oral administration of donepezil (1, 3, 10 mg/kg/day) to rats during late gestation and throughout lactation to weaning produced an increase in stillbirths and reduced offspring survival through postpartum day 4 at the highest dose.
The no-effect dose of 3 mg/kg/day is approximately 3 times the MRHD on a mg/m 2 basis.
NUSRING MOTHERS
8.2 Lactation Risk Summary There are no data on the presence of donepezil or its metabolites in human milk, the effects on the breastfed infant, or on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for donepezil hydrochloride and any potential adverse effects on the breastfed infant from donepezil hydrochloride or from the underlying maternal condition.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS • Cholinesterase inhibitors are likely to exaggerate succinylcholine-type muscle relaxation during anesthesia ( 5.1 ).
• Cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as bradycardia or heart block ( 5.2 ).
• Donepezil hydrochloride can cause vomiting.
Patients should be observed closely at initiation of treatment and after dose increases ( 5.3 ).
• Patients should be monitored closely for symptoms of active or occult gastrointestinal (GI) bleeding, especially those at increased risk for developing ulcers ( 5.4 ).
• Cholinomimetics may cause bladder outflow obstructions ( 5.6 ).
• Cholinomimetics are believed to have some potential to cause generalized convulsions ( 5.7 ).
• Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease ( 5.8 ).
5.1 Anesthesia Donepezil hydrochloride, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.
5.2 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 donepezil hydrochloride.
5.3 Nausea and Vomiting Donepezil hydrochloride, 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.
Although in most cases, these effects have been transient, sometimes lasting one to three weeks, and have resolved during continued use of donepezil hydrochloride, patients should be observed closely at the initiation of treatment and after dose increases.
5.4 Peptic Ulcer Disease and GI Bleeding 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).
Clinical studies of donepezil hydrochloride in a dose of 5 mg/day to 10 mg/day have shown no increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding.
5.6 Genitourinary Conditions Although not observed in clinical trials of donepezil hydrochloride, 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information).
Instruct patients and caregivers to take donepezil hydrochloride only once per day, as prescribed.
Instruct patients and caregivers that donepezil hydrochloride can be taken with or without food.
Advise patients and caregivers that donepezil hydrochloride may cause nausea, diarrhea, insomnia, vomiting, muscle cramps, fatigue, and decreased appetite.
Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.
Dispense with Patient Information available at: www.solcohealthcare.com/druglabeling/donepezil-tablets.pdf Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd.
Xunqiao, Linhai, Zhejiang, 317024, China Zhejiang Huahai Pharmaceutical Technology Co., Ltd.
Jiangnan, Linhai, Zhejiang 317000, China Distributed by: Solco Healthcare US, LLC Somerset, NJ 08873, USA Revised: 08/2023 200145-03 (Huahai Xunqiao) 20090-01 (Huahai Tech) Dispense with Patient Information available at: www.solcohealthcare.com/druglabeling/donepezil-tablets.pdf DONEPEZIL HYDROCHLORIDE PATIENT PACKAGE INSERT Donepezil (doe NEP e zil) Hydrochloride Tablets, USP • Tablets: 5 mg and 10 mg Read this Patient Information that comes with donepezil hydrochloride before you start taking it and each time you get a refill.
There may be new information.
This leaflet does not take the place of talking with your doctor about Alzheimer’s disease or treatment for it.
If you have questions, ask the doctor or pharmacist.
What is donepezil hydrochloride? Donepezil hydrochloride comes as donepezil hydrochloride film-coated tablets in dosage strengths of 5 mg and 10 mg.
Donepezil hydrochloride is a prescription medicine to treat mild, moderate and severe Alzheimer’s disease.
Donepezil hydrochloride can help with mental function and with doing daily tasks.
Donepezil hydrochloride does not work the same in all people.
Some people may: • Seem much better • Get better in small ways or stay the same • Get worse over time but slower than expected • Not change and then get worse as expected Donepezil hydrochloride does not cure Alzheimer’s disease.
All patients with Alzheimer’s disease get worse over time, even if they take donepezil hydrochloride.
Donepezil hydrochloride has not been approved as a treatment for any medical condition in children.
Who should not take donepezil hydrochloride? Do not take donepezil hydrochloride if you are allergic to any of the ingredients in donepezil hydrochloride tablets or to medicines that contain piperidines.
Ask your doctor if you are not sure.
See the end of this leaflet for a list of ingredients in donepezil hydrochloride tablets.
What should I tell my doctor before taking donepezil hydrochloride? Tell the doctor about all of your present or past health problems and conditions.
Include: • Any heart problems including problems with irregular, slow, or fast heartbeats • Asthma or lung problems • A seizure • Stomach ulcers • Difficulty passing urine • Liver or kidney problems • Trouble swallowing tablets • Present pregnancy or plans to become pregnant.
It is not known if donepezil hydrochloride can harm an unborn baby.
• Present breast-feeding.
It is not known if donepezil hydrochloride passes into breast milk.
Talk to your doctor about the best way to feed your baby if you take donepezil hydrochloride.
Tell the doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal products.
Donepezil hydrochloride and other medicines may affect each other.
Be particularly sure to tell the doctor if you take aspirin or medicines called nonsteroidal anti-inflammatory drugs (NSAIDs).
There are many NSAID medicines, both prescription and non-prescription.
Ask the doctor or pharmacist if you are not sure if any of your medicines are NSAIDs.
Taking NSAIDs and donepezil hydrochloride together may make you more likely to get stomach ulcers.
Donepezil hydrochloride taken with certain medicines used for anesthesia may cause side effects.
Tell the responsible doctor or dentist that you take donepezil hydrochloride before you have: • surgery • medical procedures • dental surgery or procedures Know the medicines that you take.
Keep a list of all your medicines.
Show it to your doctor or pharmacist before you start a new medicine.
How should you take donepezil hydrochloride? • Take donepezil hydrochloride exactly as prescribed by the doctor.
Do not stop donepezil hydrochloride or change the dose yourself.
Talk with your doctor first.
• Take donepezil hydrochloride one time each day.
Donepezil hydrochloride can be taken with or without food.
• If you miss giving the patient a dose of donepezil hydrochloride, just wait.
Take only the next dose at the usual time.
Do not take 2 doses at the same time.
• If donepezil hydrochloride is missed for 7 days or more, talk with your doctor before starting again.
• If you take too much donepezil hydrochloride at one time, call your doctor or poison control center, or go to the emergency room right away.
What are the possible side effects of donepezil hydrochloride? Donepezil hydrochloride may cause the following serious side effects: • slow heartbeat and fainting.
This happens more often in people with heart problems.
Call your doctor right away if you feel faint or lightheaded while taking donepezil hydrochloride.
• more stomach acid.
This raises the chance of ulcers and bleeding.
The risk is higher for people who have ulcers, or take aspirin or other NSAIDs.
• worsening of lung problems in people with asthma or other lung disease.
• seizures.
• difficulty passing urine.
Call your doctor right away if you have: • fainting.
• heartburn or stomach pain that is new or won’t go away.
• nausea or vomiting, blood in the vomit, dark vomit that looks like coffee grounds.
• bowel movements or stools that look like black tar.
• new or worse asthma or breathing problems.
• seizures.
• difficulty passing urine.
The most common side effects of donepezil hydrochloride are: • nausea • diarrhea • not sleeping well • vomiting • muscle cramps • feeling tired • not wanting to eat These side effects may get better after you take donepezil hydrochloride for a while.
This is not a complete list of side effects with donepezil hydrochloride.
For more information, ask your doctor or pharmacist.
Call your doctor for medical advice about side effects.
You may report side effects to Solco Healthcare U.
S., LLC at 1-866-257-2597 or FDA at 1-800-FDA-1088.
How should donepezil hydrochloride be stored? Store donepezil hydrochloride at room temperature between 59° to 86°F (15° to 30°C).
Keep donepezil hydrochloride and all medicines out of the reach of children.
General information about donepezil hydrochloride Medicines are sometimes prescribed for conditions that are not mentioned in this Patient Information Leaflet.
Do not use donepezil hydrochloride for a condition for which it was not prescribed.
Do not give donepezil hydrochloride to other people, even if they have the same symptoms or condition.
It may harm them.
This leaflet summarizes the most important information about donepezil hydrochloride.
If you would like more information, talk with your doctor.
You can ask your pharmacist or doctor for information about donepezil hydrochloride that is written for health professionals.
What are the ingredients in Donepezil Hydrochloride Tablets, USP? Active ingredient: donepezil hydrochloride Inactive ingredients: Donepezil Hydrochloride 5 mg and 10 mg film-coated tablets: lactose monohydrate, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, corn starch, croscarmellose sodium.
The film of 5 mg tablets coating contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, and FD&C blue.
The film of 10 mg tablets coating contains hydroxypropyl methyl cellulose, titanium dioxide, polyethylene glycol, iron oxide yellow and iron oxide red.
Rx Only Manufactured by: Zhejiang Huahai Pharmaceutical Co., Ltd.
Xunqiao, Linhai, Zhejiang, 317024, China Zhejiang Huahai Pharmaceutical Technology Co., Ltd.
Jiangnan, Linhai, Zhejiang 317000, China Distributed by: Solco Healthcare US, LLC Somerset, NJ 08873, USA Revised: 08/2023 Rx Only
DOSAGE AND ADMINISTRATION
2 • Mild to Moderate Alzheimer’s disease : 5 mg to 10 mg administered once daily ( 2.1 ) • Moderate to Severe Alzheimer’s Disease : 10 mg administered once daily ( 2.2) 2.1 Dosing in Mild to Moderate Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring.
The maximum recommended dosage of donepezil hydrochloride in patients with mild to moderate Alzheimer’s disease is 10 mg per day.
A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
2.2 Dosing in Moderate to Severe Alzheimer’s Disease The recommended starting dosage of donepezil hydrochloride is 5 mg administered once per day in the evening, just prior to retiring.
A dose of 10 mg should not be administered until patients have been on a daily dose of 5 mg for 4 to 6 weeks.
2.3 Administration Information Donepezil hydrochloride should be taken in the evening, just prior to retiring.
Donepezil hydrochloride can be taken with or without food.