Aricept

— THERAPEUTIC CATEGORIES —
  • Alzheimer's dementia
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Aricept Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Donepezil HCl 5mg, 10mg, 23mg; tabs.

    Pharmacological Class

    Reversible acetylcholinesterase inhibitor (piperidine deriv).

    See Also

    How Supplied

    Tabs 5mg, 10mg—30, 90; 23mg—30; ODT—contact supplier

    How Supplied

    Aricept Tablets

    • 5 mg tablets are supplied as white, film-coated, round tablets in 30- and 90-count bottles. The strength, in mg (5), is debossed on one side and ARICEPT is debossed on the other side.

    • 10 mg tablets are supplied as yellow, film-coated, round tablets in 30- and 90-count bottles. The strength, in mg (10), is debossed on one side and ARICEPT is debossed on the other side.

    • 23 mg tablets are supplied as reddish, film-coated, round tablets. The strength, in mg (23) is debossed on one side and ARICEPT is debossed on the other side.

    Storage

    • Store at controlled room temperature, 15°C to 30°C (59°F to 86°F).

    Manufacturer

    Eisai Pharmaceuticals

    Mechanism of Action

    Donepezil increases 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.

    Aricept Indications

    Indications

    Alzheimer's dementia.

    Aricept Dosage and Administration

    Adult

    Tabs: Swallow whole with water. ODT: dissolve on tongue, follow with water. Mild-to-moderate: Initially 5mg daily at bedtime, may increase to max 10mg daily after 4–6 weeks; usual dose: 5mg or 10mg once daily. Moderate-to-severe: initially 5mg daily at bedtime, may increase to 10mg daily after 4–6 weeks; may further increase to max 23mg daily after 3 months; usual dose: 10mg or 23mg once daily.

    Children

    Not established.

    Aricept Contraindications

    Not Applicable

    Aricept Boxed Warnings

    Not Applicable

    Aricept Warnings/Precautions

    Warnings/Precautions

    Cardiac conduction conditions. Peptic ulcer. Monitor for GI bleeding. Seizures. Asthma or COPD. GU obstruction. Body weight <55kg. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Anesthesia

    • Aricept is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia.

    Cardiovascular Conditions

    • Due to the pharmacological action, cholinesterase inhibitors may have vagotonic effects on the sinoatrial and atrioventricular nodes. This may manifest as bradycardia or heart block in patients with and without known underlying cardiac conduction abnormalities.

    • Syncopal episodes have occurred with the use of Aricept.

    Nausea and Vomiting 

    • Aricept has been associated with diarrhea, nausea, and vomiting. These effects occur more frequently with higher doses.

    • These effects are transient and sometimes last 1 to 3 weeks. Monitor patients closely during initiation and after dose increases.

    Peptic Ulcer Disease and GI Bleeding

    • May cause an increase of gastric acid secretion due to increased cholinergic activity.

    • Monitor patients closely for symptoms of active or occult GI bleeding especially those with increased risk for developing ulcers (eg, history of ulcer disease or those taking concomitant NSAIDs).

    Genitourinary Conditions

    • Cholinomimetics may cause bladder outflow obstruction, but it has not been observed in clinical trials of Aricept.

    Neurological Conditions: Seizures

    • Cholinomimetics have the potential to cause generalized convulsions, but seizure activity may also be a manifestation of Alzheimer disease.

    Pulmonary Conditions 

    • Prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

    Pregnancy Considerations

    Risk Summary

    • No adequate data on the developmental risks associated with the use of Aricept in pregnant women.

    Nursing Mother Considerations

    Risk Summary

    • No data on the presence of donepezil or its metabolites in human milk, the effects on the breastfed infant, or on milk production. 

    • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for Aricept and any potential adverse effects on the breastfed infant from Aricept or from the underlying maternal condition.

    Pediatric Considerations

    • Safety and efficacy have not been established.

    Other Considerations for Specific Populations

    Lower Weight Individuals

    • Nausea, vomiting and decreased weight occurred more in patients weighing less than 55 kg compared with patients weighing 55 kg or more.

    Aricept Pharmacokinetics

    Absorption

    • Peak plasma concentration is reached in approximately 8 hours for Aricept 23 mg tablets vs 3 hours for Aricept 10 mg tablets.

    • Steady-state is reached within 15 days.

    Distribution

    • Steady state volume of distribution: 12–16 L/kg.

    • Approximately 96% human plasma protein bound.

    Metabolism

    • Metabolized by CYP450 isoenzymes 2D6 and 3A4 and undergoes glucuronidation.

    Elimination

    • Renal (57%), fecal (15%).

    • Half-life: ~70 hours.

    • Mean apparent plasma clearance: 0.13–0.19 L/hr/kg.

    Aricept Interactions

    Interactions

    Drugs that affect CYP2D6 and CYP3A4 may affect rate of elimination. Antagonizes anticholinergics. May potentiate succinylcholine-type muscle relaxants, other cholinesterase inhibitors, cholinergic agonists (eg, bethanecol). Concomitant NSAIDs may increase risk of GI bleed.

    Aricept Adverse Reactions

    Adverse Reactions

    Nausea, diarrhea, vomiting, insomnia, muscle cramps, fatigue, anorexia, weight loss (esp. using 23mg/day dose).

    Aricept Clinical Trials

    Clinical Trials

    Mild to Moderate Alzheimer’s Disease

    The efficacy of Aricept 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 Aricept 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 Aricept 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 Aricept 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 Aricept 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 Aricept treatment groups were indistinguishable from those patients who had received only placebo for 30 weeks. The beneficial effects of Aricept 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 Aricept, 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 Aricept 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 Aricept treated patients compared to the patients on placebo were 2.7 and 3.0 points each, for the 5 and 10 mg/day Aricept 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 Aricept treatment groups increased, indicating that discontinuation of Aricept resulted in a loss of its treatment effect.

    • Effects on the CIBIC-plus

      • The differences in mean scores for Aricept 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 Aricept 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 Aricept or placebo. In the Aricept 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 Aricept 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, Aricept 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, Aricept 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 Aricept 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 Aricept 10 mg/day for at least 3 months prior to screening. Patients were randomly assigned to receive either Aricept 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.

    Aricept Note

    Not Applicable

    Aricept Patient Counseling

    See Literature

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