Donepezil Orally Disintegrating Tabs

Mild to Moderate Alzheimer’s Disease

The efficacy of donepezil hydrochloride was based on data from 2 randomized, double-blind, placebo-controlled trials 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 10 mg dose did not provide a statistically significantly greater clinical benefit than the 5 mg dose.

Study Outcome Measures

• 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 scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment. 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.

• 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.

Thirty-Week Study

• A 30-week randomized study compared donepezil hydrochloride 5 mg/day and 10 mg/day to placebo in 473 patients. The study included a 24-week double-blind active treatment phase followed by a 6-week single-blind placebo washout period. 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

• After 24 weeks, 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.

• 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. The beneficial effects of donepezil hydrochloride lessen over 6 weeks after discontinuation and do not represent a change in the underlying disease.

• Effects on the CIBIC-plus

• 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.

Fifteen-Week Study

• A 15-week randomized study compared donepezil hydrochloride 5 mg/day and 10 mg/day to placebo for 12 weeks, followed by a 3-week placebo washout period. 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

• 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 differences between active treatments were not statistically significant.

• After 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.

• Effects on the CIBIC-plus

• 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.

Moderate to Severe Alzheimer’s Disease

The efficacy of donepezil hydrochloride 10 mg/day and 23 mg/day was based on data from clinical studies in patients with moderate to severe Alzheimer’s disease. The 23 mg dose provided additional benefit in these trials compared to the 10 mg dose.

A 6-month, randomized, double-blind, placebo-controlled clinical study was conducted in Sweden in 248 patients with probable or possible Alzheimer’s disease diagnosed by NINCDS-ADRDA and DSM-IV criteria, MMSE: range of 1-10. Patients were randomly assigned to receive either donepezil hydrochloride or placebo. In the donepezil hydrochloride treatment arm, patients were initiated at 5 mg once daily for 28 days then increased to 10 mg once daily.

Study Outcome Measures

• Patients treated with donepezil hydrochloride experienced significant improvement on cognitive function and overall function compared to placebo.

• Cognitive function was assessed using the Severe Impairment Battery (SIB). 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).

• Effects on the SIB

• At 6 months of treatment, donepezil hydrochloride achieved statistically significant superiority to placebo with a mean difference in the SIB change scores compared to placebo of 5.9 points. 

• Effects on the ADCS-ADL-severe

• At 6 months of treatment, donepezil hydrochloride achieved statistically significant superiority to placebo with a mean difference in the ADCS-ADL-severe change scores compared to patients on placebo of 1.8 points.

Japanese 24-Week Study (10 mg/day)

• The 24-week study was conducted in Japan and included 325 patients with severe Alzheimer’s disease. Patients were randomly assigned to receive donepezil 5 mg/day or 10 mg/day or placebo.

• 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 efficacy of donepezil hydrochloride 23 mg/day was evaluated in 1434 patients with moderate to severe Alzheimer’s disease in a randomized, double-blind, controlled clinical trial. The study included 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. Patients were randomly assigned to receive either donepezil hydrochloride 23 mg/day or 10 mg/day.

Study Outcome Measures

• Cognitive function was assessed using the Severe Impairment Battery (SIB). Overall clinical effect was assessed using a Clinician’s Interview-Based Impression of Change that incorporated the use of caregiver information, the CIBIC-plus.

• Effects on the SIB

• At 24 weeks of treatment, the dose of 23 mg/day was statistically significantly superior to the dose of 10 mg/day with a LS mean difference in the SIB change scores compared to patients treated with 10 mg of 2.2 units (P =.0001). 

• Effects on the CIBIC-plus

• 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.