General Information

Exelon (rivastigmine tartrate) is a cholinesterase inhibitor. The exact mechanism of rivastigmine's action is unknown, however it is thought to exert its therapeutic effect by enhancing cholinergic function. It inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.

Exelon Patch is specifically indicated for the treatment of mild to moderate dementia of the Alzheimer’s type and for the treatment of mild to moderate dementia associated with Parkinson’s disease.

Exelon Patch is designed for transdermal administration. The recommended dosing and administration is as follows:

Initial Dose: Initiate treatment with one 4.6 mg/24 hours Exelon Patch applied to the skin once daily.

Dose Titration: Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been tolerated. For mild-to-moderate AD and PDD patients, continue the effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists. Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose. For patients with severe AD, 13.3 mg/24 hours is the effective dose. Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions.

In patients with mild-to-moderate Alzheimer’s Disease and mild-to-moderate Parkinson’s Disease dementia, the effective dosage of Exelon Patch is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

In patients with severe Alzheimer’s Disease, the effective dosage of Exelon Patch is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.

Interruption of Treatment If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength Exelon Patch. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours Exelon Patch and titrate as described above.

Mechanism of Action

Exelon (rivastigmine tartrate) is a cholinesterase inhibitor. The exact mechanism of rivastigmine's action is unknown, however it is thought 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 cholinesterase. Thus, rivastigmine’s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact.

Side Effects

Adverse events associated with the use of Exelon patch may include, but are not limited to, the following:

• Nausea
• Vomiting
• Diarrhea

Clinical Trial Results

The FDA approval of Exelon was based on the results of a single controlled trial in Alzheimer’s Disease as well as on three controlled trials of the immediate release capsule in Alzheimer’s Disease and one controlled trial in dementia associated with Parkinson’s Disease.

International 24-Week Study of Exelon Patch

This randomized, double-blind trial enrolled 1,195 subjects who were placed in one of the following cohorts: Exelon Patch 9.5 mg/24 hours; Exelon Patch 17.4 mg/24 hours; Exelon capsules 6 mg BID or placebo, for 24 weeks. The trial was divided into a 16-week titration phase followed by an 8-week maintenance phase. The primary endpoints included improvement from baseline in cognitive performance, assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) as well as the ability of Exelon patch to produce an overall clinical effect, assessed using the Alzheimer’s Disease Cooperative Study - Clinical Global Impression of Change (ADCS-CGIC). At 24-weeks the differences in the mean ADAS-Cog change scores for the Exelon-treated subjects compared to the subjects on placebo, were 1.8, 2.9, and 1.8 units for the Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, and Exelon capsule 6 mg BID groups, respectively. The mean differences in the ADCS-CGIC scores for the comparison of subjects in each of the Exelon-treated groups with the subjects on placebo, was 0.2 units. Both endpoints reached statistical significance compared to placebo.

International 48-Week Study in Dementia of the Alzheimer’s Type (Study 2)

This study was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State . Examination (MMSE) score greater than or equal to 10 and less than or equal to 24]. Alzheimer’s disease patients who received 24 to 48 weeks open-label treatment with Exelon Patch 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either Exelon Patch 9.5 mg/24 hours or Exelon Patch 13.3 mg/24 hours in a 48-week, double-blind treatment phase. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of greater than or equal to 2 points from the previous visit or a decrease of greater than or equal to 3 points from baseline. Study 2 was designed to compare the efficacy of Exelon Patch 13.3 mg/24 hours versus that of Exelon Patch 9.5 mg/24 hours during the 48-week, double-blind treatment phase. Decline in the mean ADCSIADL score from the double-blind baseline for the Intent to Treat-Last Observation Carried Forward (ITT-LOCF) analysis was less at each timepoint in the 13.3 mg/24 hour Exelon Patch treatment group than in the 9.5 mg/24 hours Exelon Patch treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint). The between-treatment group difference for Exelon Patch 13.3 mg/24 hours versus Exelon Patch 9.5 mg/24 hours was nominally statistically significant at week 24, but not at week 48, which was the primary endpoint.

24-Week United States Study With EXELON PATCH in Severe Alzheimer’s Disease (Study 3)

This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 3 and less than or equal to 12]. The study was designed to compare the efficacy of Exelon Patch 13.3 mg/24 hours versus that of Exelon Patch 4.6 mg/24 hours during the 24-week double-blind treatment phase. Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours Exelon Patch treatment group than in the 4.6 mg/24 hours Exelon Patch treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint). Decline in the mean ADCS-ADLSIV score from baseline for the MFAS-LOCF analysis was less at each timepoint in the 13.3 mg/24 hours Exelon Patch treatment group than in the 4.6 mg/24 hours Exelon Patch treatment group. The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).