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Exelon Patch

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Exelon Patch

CLINICAL PHARMACOLOGY

Mechanism of Action

Although the precise mechanism of action of rivastigmine is unknown, 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. The effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process.

Pharmacodynamics

After a 6-mg oral dose of rivastigmine in humans, anticholinesterase activity is present in cerebrospinal fluid for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing.

In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.

Pharmacokinetics

Absorption

After the initial application of Exelon Patch, there is a lag time of 0.5 to 1 hour in the absorption of rivastigmine. Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (Cmax) can also occur later (at 10 to 16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady state, trough levels are approximately 60 to 80% of peak levels.

Exelon Patch 9.5 mg/24 hours gave exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day). Inter-subject variability in exposure was lower (43 to 49%) for the Exelon Patch formulation as compared with the oral formulations (73 to 103%). Fluctuation (between Cmax and Cmin) is less for Exelon Patch than for the oral formulation of rivastigmine.

Figure 2 displays rivastigmine plasma concentrations over 24 hours for the three available patch strengths.

Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application

Rivastigmine plasma concentrations over 24 hours - Illustration

Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system.

Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the three other sites is available, but the practitioner should be aware that the rivastigmine plasma exposure associated with these sites was approximately 20 to 30% lower.

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer's disease with daily dosing.

The pharmacokinetic profile of rivastigmine transdermal patches was comparable in patients with Alzheimer's disease and in patients with dementia associated with Parkinson's disease.

Distribution

Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg.

Metabolism

Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase ( < 10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism.

The metabolite-to-parent AUC∞ ratio was about 0.7 after Exelon Patch application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin.

Elimination

Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete ( > 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1 to 2.8 L/hr.

Renal Impairment

No study was conducted with Exelon Patch in subjects with renal impairment. Based on population analysis creatinine clearance did not show any clear effect on steady state concentrations of rivastigmine or its metabolite. No dosage adjustment is necessary in patients with renal impairment.

Hepatic Impairment

No pharmacokinetic study was conducted with Exelon Patch in subjects with hepatic impairment. After multiple 6-mg twice daily oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10) [see DOSAGE AND ADMINISTRATION, Specific Population].

Body Weight

A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer's dementia patients. Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved [see DOSAGE AND ADMINISTRATION].

Age

Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with Exelon Patch.

Gender or Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Exelon Patch. A population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 White, 34 Black, 4 Asian, and 12 Other) affected clearance of the drug. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of Exelon Patch.

Smoking

Population pharmacokinetic analysis showed that nicotine use increased the oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers).

Drug Interaction Studies

No specific interaction studies have been conducted with Exelon Patch. Information presented below is from studies with oral rivastigmine.

Effect of Rivastigmine on the Metabolism of Other Drugs

Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6.

No pharmacokinetic interaction was observed between rivastigmine taken orally and digoxin, warfarin, diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine.

Effect of Other Drugs on the Metabolism of Rivastigmine

Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine.

Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), -blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35), and antihistamines (n=15).

Clinical Studies

The effectiveness of the Exelon Patch in dementia of the Alzheimer's type and dementia associated with Parkinson's disease was based on the results of three controlled trials of Exelon Patch in patients with Alzheimer's disease (Studies 1, 2, and 3) (see below); three controlled trials of oral rivastigmine in patients with dementia of the Alzheimer's type; and one controlled trial of oral rivastigmine in patients with dementia associated with Parkinson's disease. See the prescribing information for oral rivastigmine for details of the four studies of oral rivastigmine.

Mild to Moderate Alzheimer's Disease

International 24-Week Study of Exelon Patch in Dementia of the Alzheimer's Type (Study 1)

This study was a randomized double-blind, double dummy clinical investigation in patients with Alzheimer's disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score ≥ 10 and ≤ 20] (Study 1). The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years. Approximately 67% of patients were women, and 33% were men. The racial distribution was White 75%, Black 1%, Asian 9%, and other races 15%.

The effectiveness of the Exelon Patch was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect.

The ability of the Exelon Patch 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 ability of the Exelon Patch to produce an overall clinical effect was assessed using the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The ADCS-CGIC is a more standardized form of the Clinician's Interview-Based Impression Of Change-Plus (CIBIC-Plus) and is also scored as a seven-point categorical rating; scores range from 1, indicating “markedly improved,” to 4, indicating “no change,” to 7, indicating “marked worsening.”

In Study 1, 1195 patients were randomized to one of the following four treatments: Exelon Patch 9.5 mg/24 hours, Exelon Patch 17.4 mg/24 hours, Exelon capsules in a dose of 6 mg twice daily, or placebo. This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase. In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.

Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study. At 24 weeks, the mean differences in the ADAS-Cog change scores for the Exelontreated patients compared to the patients 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 twice daily groups, respectively. The difference between each of these groups and placebo was statistically significant. Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation (see Figure 4).

Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 1

Time Course of the Change from Baseline in ADAS-Cog Score - Illustration

Figure 4 presents the distribution of patients' scores on the ADCS-CGIC for all 4 treatment groups. At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the Exelon-treated groups with the patients on placebo was 0.2 units. The difference between each of these groups and placebo was statistically significant.

Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing Study 1

Distribution of ADCS-CGIC Scores - Illustration

International 48-Week Study of Exelon Patch 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 ≥ 10 and ≤ 24] (Study 2). The mean age of patients participating in this trial was 76 years with a range of 50-85 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 97%, Black 2%, Asian 0.5%, and other races 1%. Approximately 27% of the patients were taking memantine throughout the entire duration of the study.

Alzheimer's disease patients who received 24 to 48 weeks open label treatment with Exelon Patch 9.5mg/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 ≥ 2 points from the previous visit or a decrease of ≥ 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.

The ability of the Exelon Patch 13.3 mg/24 hours to improve cognitive performance over that provided by the Exelon Patch 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) [see International 24-Week Study].

The ability of the Exelon Patch 13.3 mg/24 hours to improve overall function versus that provided by Exelon Patch 9.5 mg/24 hours was assessed by the instrumental sub-scale of the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-IADL). The ADCS-IADL sub-scale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale. The ADCS-IADL assesses activities such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests. A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.

Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study. Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours Exelon Patch treatment group and 280 patients entered the 13.3 mg/24 hours Exelon Patch treatment group.

Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study. 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).

Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase. 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 (p=0.027), but not at week 48 (p=0.227), which was the primary endpoint.

Figure 5: Time Course of the Change from Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2

Time Course of the Change from Double-Blind Baseline in ADCS-IADL Score - Illustration

Figure 6: Time Course of the Change from Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2

Time Course of the Change from Double-Blind Baseline in ADAS-Cog Score - Illustration

Severe Alzheimer's Disease

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 ≥ 3 and ≤ 12]. The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged > 75 years. Approximately 65% of patients were women and 35% were men. The racial distribution was approximately Caucasian 87%, Black 7%, Asian 1%, and other races 5%. Patients on a stable dose of memantine were permitted to enter the study. Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study.

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.

The ability of the 13.3 mg/24 hours Exelon Patch to improve cognitive performance versus that provided by the 4.6 mg/24 hours Exelon Patch was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients. The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name. The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.

The ability of the 13.3 mg/ 24 hours Exelon Patch to improve overall function versus that provided by the 4.6 mg/24 hours Exelon Patch was assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living – Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions. A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment.

In this study, 716 patients were randomized into one of the following treatments: Exelon Patch 13.3 mg/24 hours or Exelon Patch 4.6 mg/24 hours in a 1:1 ratio. This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase. In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.

Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study. 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 time point in the 13.3 mg/24 hour 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 4.6mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study. 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 hour 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 4.6mg/24 hours dose at weeks 16 and 24 (primary endpoint).

Figure 7: Time Course of the Change from Baseline in SIB Score for Patients Observed at Each Time Point (Modified Full Analysis Set–LOCF)

Time Course of the Change from Baseline in SIB Score - Illustration

Figure 8: Time Course of the Change from Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified Full Analysis Set–LOCF)

Time Course of the Change from Baseline in ADCS-ADL-SIV Score for Patients - Illustration

Last reviewed on RxList: 7/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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