Donepezil

Drugs with anti-cholinergic properties that counteract donepezil and should be avoided include:

• Bentropine (Cogentin)
• Atropine (Atropine Sulfate)
• Trihexyphenidyl (Artane)

The following medications, which increase enzymes in the liver, may reduce the effect of donepezil:

• Phenobarbital (Luminal)
• Phenytoin (Dilantin)
• Rifampin (Rifadin)
• Carbamazepine (Tegretol)
• Dexamethasone (Decadron)

There are other medications, both prescription and over-the-counter (OTC), that interact with donepezil. It's important to tell your doctor all of the medications you are taking.

The most common side effects associated with donepezil are:

• headache,
• generalized pain,
• fatigue,
• dizziness,
• nausea,
• vomiting,
• diarrhea,
• loss of appetite,
• weight loss,
• muscle cramping,
• joint pain,
• insomnia, and
• increased frequency of urination.

Other important side effects include:

• seizures,
• fainting,
• abnormal heart beats, and
• stomach ulcers.

It is not known whether donepezil is excreted into human breast milk or if it will harm a nursing child.

If you take too much donepezil, call your doctor or local Poison Control Center right away.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include severe nausea, vomiting, drooling, sweating, blurred vision, feeling light-headed, slow heartbeat, shallow breathing, muscle weakness, fainting, or seizure (convulsions).

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with donepezil, especially:

• NSAIDs (nonsteroidal anti-inflammatory drugs)--aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others;

This list is not complete. Other drugs may interact with donepezil, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Donepezil is used to treat dementia (memory loss and mental changes) associated with mild, moderate, or severe Alzheimer's disease. Donepezil will not cure Alzheimer's disease, and it will not stop the disease from getting worse. However, it can improve thinking ability in some patients.

donepezil is available only with your doctor's prescription.

It is important that your doctor check your progress at regular visits. This is necessary to allow dose adjustments and to reduce any unwanted effects.

Before you have any kind of surgery, dental treatment, or emergency treatment, tell the medical doctor or dentist in charge that you are using donepezil. Taking donepezil together with certain medicines that are used during surgery or dental or emergency treatments may increase the effects of those medicines and cause unwanted effects.

donepezil may cause some people to become dizzy or drowsy, to have blurred vision, or to have problems with clumsiness or unsteadiness. Make sure you know how you react to donepezil before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, and able to see clearly.

Some people who have used donepezil developed problems such as nausea, severe vomiting, loss of appetite, diarrhea, and weight loss. Talk with your doctor before using donepezil if you have any concerns.

Tell you doctor right away if you have bloody or black tarry stools, constipation, severe stomach pain, or vomiting of blood or material that looks like coffee grounds. These may be symptoms of stomach or bowel bleeding.

If you think that you or someone else may have taken an overdose of donepezil, get emergency help at once. Taking an overdose of donepezil may cause convulsions (seizures) or serious effects on your heart and your breathing. Signs of overdose include increased watering of mouth, increased sweating, low blood pressure, muscle weakness, severe nausea, severe vomiting, slow heartbeat, and troubled breathing.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

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.

Pharmacokinetics

Pharmacokinetics of Donepezil are linear over a dose range of 1-10 mg given once daily. The rate and extent of absorption of Donepezil hydrochloride tablets are not influenced by food.

Based on population pharmacokinetic analysis of plasma Donepezil concentrations measured in patients with Alzheimer's disease, following oral dosing, peak plasma concentration is achieved for Donepezil hydrochloride 23 mg tablets in approximately 8 hours, compared with 3 hours for Donepezil hydrochloride 10 mg tablets. Peak plasma concentrations were about 2-fold higher for Donepezil hydrochloride 23 mg tablets than Donepezil hydrochloride 10 mg tablets.

Donepezil hydrochloride ODT 5 mg and 10 mg are bioequivalent to Donepezil hydrochloride 5 mg and 10 mg tablets, respectively. A food effect study has not been conducted with Donepezil hydrochloride ODT; however, the effect of food with Donepezil hydrochloride ODT is expected to be minimal. Donepezil hydrochloride ODT can be taken without regard to meals.

The elimination half life of Donepezil is about 70 hours, and the mean apparent plasma clearance (Cl/F) is 0.13-0.19 L/hr/kg. Following multiple dose administration, Donepezil accumulates in plasma by 4-7 fold, and steady state is reached within 15 days. The steady state volume of distribution is 12-16 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (about 75%) and alpha1 - acid glycoprotein (about 21%) over the concentration range of 2-1000 ng/mL.

Donepezil is both excreted in the urine intact and extensively metabolized to four major metabolites, two of which are known to be active, and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by CYP 450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation. Following administration of 14C-labeled Donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact Donepezil (53%) and as 6-O-desmethyl Donepezil (11%), which has been reported to inhibit AChE to the same extent as Donepezil in vitro and was found in plasma at concentrations equal to about 20% of Donepezil. Approximately 57% and 15% of the total radioactivity was recovered in urine and feces, respectively, over a period of 10 days, while 28% remained unrecovered, with about 17% of the Donepezil dose recovered in the urine as unchanged drug. Examination of the effect of CYP2D6 genotype in Alzheimer's patients showed differences in clearance values among CYP2D6 genotype subgroups. When compared to the extensive metabolizers, poor metabolizers had a 31.5% slower clearance and ultra-rapid metabolizers had a 24% faster clearance.

Hepatic Disease

In a study of 10 patients with stable alcoholic cirrhosis, the clearance of Donepezil hydrochloride was decreased by 20% relative to 10 healthy age-and sex-matched subjects.

Renal Disease

In a study of 11 patients with moderate to severe renal impairment (ClC < 18 mL/min/1.73 m2) the clearance of Donepezil hydrochloride did not differ from 11 age-and sex-matched healthy subjects.

Age

No formal pharmacokinetic study was conducted to examine age-related differences in the pharmacokinetics of Donepezil hydrochloride. Population pharmacokinetic analysis suggested that the clearance of Donepezil in patients decreases with increasing age. When compared with 65-year old, subjects, 90-year old subjects have a 17% decrease in clearance, while 40-year old subjects have a 33% increase in clearance. The effect of age on Donepezil clearance may not be clinically significant.

Gender and Race

No specific pharmacokinetic study was conducted to investigate the effects of gender and race on the disposition of Donepezil hydrochloride. However, retrospective pharmacokinetic analysis and population pharmacokinetic analysis of plasma Donepezil concentrations measured in patients with Alzheimer's disease indicates that gender and race (Japanese and Caucasians) did not affect the clearance of Donepezil hydrochloride to an important degree.

Body Weight

There was a relationship noted between body weight and clearance. Over the range of body weight from 50 kg to 110 kg, clearance increased from 7.77 L/h to 14.04 L/h, with a value of 10 L/hr for 70 kg individuals.

Drug Interactions

Effect of Donepezil hydrochloride on the Metabolism of Other Drugs

No in vivo clinical trials have investigated the effect of Donepezil hydrochloride on the clearance of drugs metabolized by CYP 3A4 (e.g., cisapride, terfenadine) or by CYP 2D6 (e.g., imipramine). However, in vitro studies show a low rate of binding to these enzymes (mean Ki about 50-130 µM), that, given the therapeutic plasma concentrations of Donepezil (164 nM), indicates little likelihood of interference. Based on in vitro studies, Donepezil shows little or no evidence of direct inhibition of CYP2B6, CYP2C8, and CYP2C19 at clinically relevant concentrations.

Whether Donepezil hydrochloride has any potential for enzyme induction is not known. Formal pharmacokinetic studies evaluated the potential of Donepezil hydrochloride for interaction with theophylline, cimetidine, warfarin, digoxin, and ketoconazole. No effects of Donepezil hydrochloride on the pharmacokinetics of these drugs were observed.

Effect of Other Drugs on the Metabolism of Donepezil hydrochloride

Ketoconazole and quinidine, strong inhibitors of CYP450 3A and 2D6, respectively, inhibit Donepezil metabolism in vitro. Whether there is a clinical effect of quinidine is not known. Population pharmacokinetic analysis showed that in the presence of concomitant CYP2D6 inhibitors Donepezil AUC was increased by approximately 17% to 20% in Alzheimer's disease patients taking Donepezil hydrochloride 10 and 23 mg. This represented an average effect of weak, moderate, and strong CYP2D6 inhibitors. In a 7-day crossover study in 18 healthy volunteers, ketoconazole (200 mg q.d.) increased mean Donepezil (5 mg q.d.) concentrations (AUC0-24 and Cmax) by 36%. The clinical relevance of this increase in concentration is unknown.

Inducers of CYP 3A (e.g., phenytoin, carbamazepine, dexamethasone, rifampin, and phenobarbital) could increase the rate of elimination of Donepezil hydrochloride.

Formal pharmacokinetic studies demonstrated that the metabolism of Donepezil hydrochloride is not significantly affected by concurrent administration of digoxin or cimetidine.

An in vitro study showed that Donepezil was not a substrate of P-glycoprotein.

Drugs Highly Bound to Plasma Proteins

Drug displacement studies have been performed in vitro between this highly bound drug (96%) and other drugs such as furosemide, digoxin, and warfarin. Donepezil hydrochloride at concentrations of 0.3-10 micrograms/mL did not affect the binding of furosemide (5 micrograms/mL), digoxin (2 ng/mL), and warfarin (3 micrograms/mL) to human albumin. Similarly, the binding of Donepezil hydrochloride to human albumin was not affected by furosemide, digoxin, and warfarin.

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%.

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.

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 30week 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%.

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.

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 and 23 mg/day. Results of a controlled clinical trial in moderate to severe Alzheimer's Disease that compared Donepezil hydrochloride 23 mg once daily to 10 mg once daily suggest that a 23 mg dose of Donepezil hydrochloride provided additional benefit.

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.

Effect 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.

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.

Study of 23 mg/day

The effectiveness of Donepezil hydrochloride 23 mg/day as a treatment for moderate to severe Alzheimer's disease has been demonstrated by the results of a randomized, double-blind, controlled clinical investigation in patients with moderate to severe Alzheimer's disease. The controlled clinical study was conducted globally in patients with probable Alzheimer's disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 0-20. Patients were required to have been on a stable dose of Donepezil hydrochloride 10 mg/day for at least 3 months prior to screening. One thousand four hundred and thirty four (1434) patients with moderate to severe Alzheimer's disease were randomized to 23 mg/day or 10 mg/day. The mean age of patients was 73.8 years, with a range of 47 to 90. Approximately 63% of patients were women, and 37% were men. Approximately 36% of the patients were taking memantine throughout the study.

Study Outcome Measures

The effectiveness of treatment with 23 mg/day 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.

The ability of 23 mg/day 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.

The ability of 23 mg/day to produce an overall clinical effect was assessed using a Clinician's Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus. The CIBIC-plus used in this trial was a semi-structured instrument that examines 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."

Effects on the SIB

Figure 11 shows the time course for the change from baseline in SIB score for the two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the LS mean difference in the SIB change scores for 23 mg/day-treated patients compared to patients treated with 10 mg was 2.2 units (p = 0.0001). The dose of 23 mg/day was statistically significantly superior to the dose of 10 mg/day.

Figure 11. Time-course of the Change from Baseline in SIB Score for Patients Completing 24 Weeks of Treatment.

Figure 12 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 23 mg/day and to 10 mg/day have a wide range of responses, the curves show that the 23 mg-group is more likely to show a greater improvement in cognitive performance. When such curves are shifted to the left, this indicates a greater percentage of patients responding to treatment on the SIB.

Figure 12. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment with Specified Changes from Baseline SIB Scores.

Effects on the CIBIC-plus

Figure 13 is a histogram of the frequency distribution of CIBIC-plus scores attained by patients at the end of 24 weeks of treatment. The mean difference between the 23 mg/day and 10 mg/day treatment groups was 0.06 units. This difference was not statistically significant.

Figure 13. Frequency Distribution of CIBIC-plus Scores at Week 24.

There are no dosage adjustments provided in the manufacturer’s labeling. Limited data suggest severe renal impairment does not adversely affect donepezil clearance.

Concerns related to adverse effects:

• Altered cardiac conduction: Donepezil may be associated with QT prolongation and torsades de pointes; use with caution in patients at risk of prolonged cardiac repolarization (Howes 2014). Cholinesterase inhibitors may have vagotonic effects which may cause bradycardia and/or heart block in patients with or without a history of cardiac disease; syncopal episodes have been associated with donepezil. Use with caution in patients with sick-sinus syndrome, bradycardia, or conduction abnormalities. Alzheimer treatment guidelines consider bradycardia to be a relative contraindication for use of centrally active cholinesterase inhibitors (APA [Rabins 2007]).

• Anorexia/weight loss: May cause anorexia and/or weight loss (dose-related).

• GI effects: May cause dose-related diarrhea, nausea, and/or vomiting; usually resolves in 1 to 3 weeks.

• Neuroleptic malignant syndrome: Rare cases of neuroleptic malignant syndrome (NMS) have been reported (Matsumoto 2004; Warwick 2008). Discontinuation of donepezil therapy may be necessary in patients presenting with symptoms of NMS (eg, hyperthermia, irregular pulse or blood pressure, cardiac arrhythmia, diaphoresis, muscle rigidity, mental status changes, elevated creatine phosphokinase [CPK], or unexplained high fever without additional symptoms).

• Rhabdomyolysis: Rare cases of rhabdomyolysis (including acute renal failure) have been reported after a few months of therapy (Sahin 2014) or in the days following therapy initiation and dose increase (Aricept Canadian product monograph 2014). Use with caution in patients with risk factors for rhabdomyolysis (eg, concomitant medications associated with rhabdomyolysis, history of muscular disorders, uncontrolled hypothyroidism, renal/hepatic impairment). Discontinuation of therapy may be necessary for marked elevation of CPK levels and/or symptoms (eg, muscle pain, tenderness or weakness, malaise, fever, dark urine) suggesting rhabdomyolysis.

Disease-related concerns:

• Peptic ulcer disease: Use with caution in patients at risk of ulcer disease (eg, previous history or NSAID use); cholinesterase inhibitors may increase gastric acid secretion. Monitor for symptoms of bleeding.

• Respiratory disease: Use with caution in patients with COPD and/or asthma.

• Seizure disorder: Use with caution in patients with a history of seizure disorder; cholinomimetics may potentially cause generalized seizures, although seizure activity may also result from Alzheimer disease.

• Urinary tract obstruction: Use with caution in patients with bladder outlet obstruction or prostatic hyperplasia; cholinomimetics may cause or worsen outflow obstructions, including possible exacerbation of BPH symptoms (APA [Rabins 2007]).

Special populations:

• Low-weight patients: Patients weighing <55 kg may experience more nausea, vomiting, and weight loss than patients ≥55 kg.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Aspartame: Some products may contain aspartame, which is metabolized to phenylalanine and must be avoided (or used with caution) in patients with phenylketonuria.

Mental status, weight, symptoms of GI intolerance, symptoms of active or occult GI bleeding.

Data not available