July 30, 2016
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Exelon Patch

"The US Food and Drug Administration (FDA) has approved a fixed-dose combination of memantine hydrochloride extended-release (XR) and donepezil hydrochloride (Namzaric, Actavis plc/Adamas Pharm) for moderate to severe Alzheimer's-related de"...

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Exelon Patch




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SIDE EFFECTS

The following adverse reactions are described below and elsewhere in the labeling:

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

EXELON PATCH has been administered to 4516 patients with Alzheimer's disease during clinical trials worldwide. Of these, 3005 patients have been treated for at least 26 weeks, 1771 patients have been treated for at least 52 weeks, 974 patients have been treated for at least 78 weeks and 24 patients have been treated for at least 104 weeks.

Mild to Moderate Alzheimer's Disease

24-Week International Placebo-Controlled Trial (Study 1)

Most Common Adverse Reactions

The most common adverse reactions in patients administered EXELON PATCH in Study 1 [see Clinical Studies], defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours EXELON PATCH arm and at a frequency at higher than in the placebo group, were nausea, vomiting, and diarrhea. These reactions were dose-related, with each being more common in patients using the unapproved 17.4 mg/24 hours EXELON PATCH than in those using the 9.5 mg/24 hours EXELON PATCH.

Discontinuation Rates

In Study 1, which randomized a total of 1195 patients, the proportions of patients in the EXELON PATCH 9.5 mg/24 hours, EXELON Capsules 6 mg twice daily, and placebo groups who discontinued treatment due to adverse events were 10%, 8%, and 5%, respectively.

The most common adverse reactions in the EXELON PATCH-treated groups that led to treatment discontinuation in this study were nausea and vomiting. The proportions of patients who discontinued treatment due to nausea were 0.7%, 1.7%, and 1.3% in the EXELON PATCH 9.5 mg/24 hours, EXELON Capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2.0%, and 0.3% in the EXELON PATCH 9.5 mg/24 hours, EXELON Capsules 6 mg twice daily, and placebo groups, respectively.

Adverse Reactions Observed at an Incidence of ≥ 2%

Table 1 lists adverse reactions seen at an incidence of ≥ 2% in either EXELON PATCH-treated group in Study 1 and for which the rate of occurrence was greater for patients treated with that dose of EXELON PATCH than for those treated with placebo. The unapproved 17.4 mg/24 hours EXELON PATCH arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours EXELON PATCH.

Table 1: Proportion of Adverse Reactions Observed with a Frequency of ≥ 2% and Occurring at a Rate Greater Than Placebo in Study 1

  EXELON PATCH 9.5 mg/24 hours EXELON PATCH 17.4 mg/24 hours EXELON Capsule 6 mg twice daily Placebo
Total Patients Studied 291 303 294 302
Total Percentage of Patients with ARs (%) 51 66 63 46
Nausea 7 21 23 5
Vomiting* 6 19 17 3
Diarrhea 6 10 5 3
Depression 4 4 4 1
Headache 3 4 6 2
Anxiety 3 3 2 1
Anorexia/Decreased Appetite 3 9 9 2
Weight Decreased** 3 8 5 1
Dizziness 2 7 7 2
Abdominal Pain 2 4 1 1
Urinary Tract Infection 2 2 1 1
Asthenia 2 3 6 1
Fatigue 2 2 1 1
Insomnia 1 4 2 2
Abdominal Pain Upper 1 3 2 2
Vertigo 0 2 1 1
*Vomiting was severe in 0% of patients who received EXELON PATCH 9.5 mg/24 hours, 1% of patients who received EXELON PATCH 17.4 mg/24 hours, 1% of patients who received the EXELON Capsule at doses up to 6 mg twice daily, and 0% of those who received placebo.
**Weight Decreased as presented in Table 1 is based upon clinical observations and/or adverse events reported by patients or caregivers. Body weight was also monitored at prespecified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 8% of those treated with EXELON PATCH 9.5 mg/24 hours, 12% of those treated with EXELON PATCH 17.4 mg/24 hours, 11% of patients who received the EXELON Capsule at doses up to 6 mg twice daily and 6% of those who received placebo. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.

48-Week International Active Comparator-Controlled Trial (Study 2)

Most Common Adverse Reactions

In Study 2 [see Clinical Studies] of the commonly observed adverse reactions ( ≥ 3% in any treatment group) the most frequent event in the EXELON PATCH 13.3 mg/24 hours group was nausea, followed by vomiting, fall, weight decreased, application site erythema, decreased appetite, diarrhea and urinary tract infection (Table 3). The percentage of patients with these events was higher in the EXELON PATCH 13.3 mg/24 hours group than in the EXELON PATCH 9.5 mg/24 hours group. Patients with nausea, vomiting, diarrhea and decreased appetite experienced these reactions more often during the first 4 weeks of the double-blind treatment phase. These reactions decreased over time in each treatment group. Weight decreased was reported to have increased over time in each treatment group.

Discontinuation Rates

Table 2 displays the most common adverse reactions leading to discontinuation during the 48-week, double-blind treatment phase in Study 2.

Table 2: Proportion of Most Common Adverse Reactions ( > 1% at Any Dose) Leading to Discontinuation During 48-week Double-Blind Treatment Phase in Study 2

  EXELON PATCH 13.3 mg/24 hours EXELON PATCH 9.5 mg/24 hours Total
Total Patients Studied 280 283 563
Total Percentage of Patients with ARs Leading to Discontinuation (%) 9.6 12.7 11.2
Vomiting 1.4 0.4 0.9
Application site pruritus 1.1 1.1 1.1
Aggression 0.4 1.1 0.7

Most Common Adverse Reactions ≥ 3%

Other adverse reactions of interest which occurred less frequently, but which were observed in a markedly higher percentage of patients in the EXELON PATCH 13.3 mg/24 hours group than in the EXELON PATCH 9.5 mg/24 hours group in Study 2, included dizziness and upper abdominal pain. The percentage of patients with these reactions decreased over time in each treatment group (Table 3). The adverse reaction severity profile was generally similar for both the EXELON PATCH 13.3 mg/24 hours and 9.5 mg/24 hours groups.

Table 3: Proportion of Adverse Reactions Over Time in the 48-week Double-Blind (DB) Treatment Phase (at Least 3% in any Treatment Group) in Study 2

Preferred Term Cumulative Week 0 to 48 (DB Phase) Week 0 to 24 (DB Phase) Week > 24 to 48 (DB Phase)
EXELON PATCH 13.3 mg/24 hours EXELON PATCH 9.5 mg/24 hours EXELON PATCH 13.3 mg/24 hours EXELON PATCH 9.5 mg/24 hours EXELON PATCH 13.3 mg/24 hours EXELON PATCH 9.5 mg/24 hours
Total Patients Studied 280 283 280 283 241 246
Total Percentage of Patients with ARs (%) 75 68 65 55 42 40
Nausea 12 5 10 4 4 2
Vomiting 10 5 9 3 3 2
Fall 8 6 4 4 4 3
Weight decreased* 7 3 3 1 5 2
Application site erythema 6 6 6 5 1 2
Decreased appetite 6 3 5 2 2 < 1
Diarrhea 6 5 5 4 2 < 1
Urinary tract infection 5 4 3 3 3 2
Agitation 5 5 4 3 1 2
Depression 5 5 3 3 3 2
Dizziness 4 1 3 < 1 2 < 1
Application site pruritus 4 4 4 3 < 1 1
Headache 4 4 4 4 < 1 < 1
Insomnia 4 3 2 1 3 2
Abdominal pain upper 4 1 3 1 1 < 1
Anxiety 4 3 2 2 2 1
Hypertension 3 3 3 2 1 1
Urinary incontinence 3 2 2 1 1 < 1
Psychomotor hyperactivity 3 3 2 3 2 1
Aggression 2 3 1 3 1 1
*Decreased Weight as presented in Table 3 is based upon clinical observations and/or adverse events reported by patients or caregivers. Body weight was monitored as a vital sign at pre-specified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 15.2% of those treated with EXELON PATCH 9.5 mg/24 hours and 18.6% of those treated with EXELON PATCH 13.3 mg/24 hours during the 48-week double-blind treatment period.

Severe Alzheimer's Disease

24-Week US Controlled Trial (Study 3)

Most Commonly Observed Adverse Reactions

The most common adverse reactions in patients administered EXELON PATCH in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 13.3 mg/24 hours EXELON PATCH arm and at a frequency higher than in the 4.6 mg/24 hours EXELON PATCH were application site erythema, fall, insomnia, vomiting, diarrhea, weight decreased, and nausea (Table 4). Patients in the lower dose group reported more events of agitation, urinary tract infection, and hallucinations than patients in the higher dose group.

Discontinuation Rates

In Study 3 [see Clinical Studies], the proportions of patients in the EXELON PATCH 13.3 mg/24 hours (n=355) and EXELON PATCH 4.6 mg/24 hours (n=359), who discontinued treatment due to adverse reactions were 21% and 14%, respectively.

The most frequent adverse reaction leading to discontinuation in the 13.3 mg/24 hours treatment group versus the 4.6 mg/24 hours treatment group was agitation (2.8% versus 2.2%), followed by vomiting (2.5% and 1.1%), nausea (1.7% and 1.1%), decreased appetite (1.7% and 0%), aggression (1.1% and 0.3%), fall (1.1% and 0.3%) and syncope (1.1% and 0.3%). Otherwise, all AEs leading to discontinuation were reported in < 1% of patients.

Most Commonly Observed Adverse Reactions ≥ 5%

Other adverse reactions of interest which were observed in a higher percentage of patients in the EXELON PATCH 13.3 mg/24 hours group than in the EXELON PATCH 4.6 mg/24 hours group, included application site erythema, fall, insomnia, vomiting, diarrhea, weight decreased, and nausea (Table 4). Overall, the majority of patients in this study experienced adverse reactions that were mild (30.7%) or moderate (32.1%) in severity. Slightly more patients in the 4.6 mg/24 hours patch group reported mild events than in the 13.3 mg/24 hours patch group, while the numbers of patients reporting moderate events were comparable between groups. Severe adverse reactions were reported at a slightly higher percentage at the higher dose (12.4%) than at the lower dose (10%) treatment groups. With the exception of severe adverse reactions of agitation (13.3 mg: 1.1%; 4.6 mg: 1.4%), fall (13.3 mg: 1.1%) and urinary tract infection (4.6 mg: 1.1%), all adverse reactions reported as severe occurred in less than 1% of patients in either treatment group.

Table 4: Proportion of Adverse Reactions in the 24-week Double-Blind (DB) Treatment Phase (at Least 5% in Any Treatment Group) in Study 3

Preferred term EXELON PATCH 13.3 mg/24 hours EXELON PATCH 4.6 mg/24 hours
Total number of patients studied 355 359
Total percentage of patients with ARs (%) 75 73
Application site erythema 13 12
Agitation 12 14
Urinary tract infection 8 10
Fall 8 6
Insomnia 7 4
Vomiting 7 3
Diarrhea 7 5
Weight decreased* 7 3
Nausea 6 3
Depression 5 4
Decreased appetite 5 1
Anxiety 5 5
Hallucination 2 5
*Weight Decreased as presented in Table 4 is based upon clinical observations and/or adverse events reported by patients or caregivers. Body weight was monitored as a vital sign at prespecified time points throughout the course of the clinical study. The proportion of patients who had weight loss equal to or greater than 7% of their baseline weight was 11% of those treated with EXELON PATCH 4.6 mg/24 hours and 14.1% of those treated with EXELON PATCH 13.3 mg/24 hours during the 24-week double-blind treatment.

Application Site Reactions

Application site skin reactions leading to discontinuation were observed in &e;2.3% of EXELON PATCH patients. This number was 4.9% and 8.4% in the Chinese population and Japanese population, respectively.

Cases of skin irritation were captured separately on an investigator-rated skin irritation scale. Skin irritation, when observed, was mostly slight or mild in severity and was rated as severe in &e;2.2% of EXELON PATCH patients in a double-blind controlled study and in &e;3.7% of EXELON PATCH patients in a double-blind controlled study in Japanese patients.

Parkinson's Disease Dementia

76-week International Open-Label Trial (Study 4)

EXELON PATCH has been administered to 288 patients with mild to moderate Parkinson's Disease Dementia in a single, 76-week, open-label, active-comparator safety study. Of these, 256 have been treated for at least 12 weeks, 232 for at least 24 weeks, and 196 for at least 52 weeks.

Treatment with EXELON PATCH was initiated at 4.6 mg/24 hours and if tolerated the dose was increased after 4 weeks to 9.5 mg/24 hours. EXELON Capsule (target maintenance dose of 12 mg/day) served as the active comparator and was administered to 294 patients. Adverse reactions are presented in Table 5.

Table 5: Proportion of Adverse Reactions Reported at a Rate ≥ 2% During the Initial 24-Week Period in Study 4

Adverse drug reactions EXELON PATCH
Total patients studied 288
  Percentage (%)
Psychiatric disorders
Insomnia 6
Depression 6
Anxiety 5
Agitation 3
Nervous system disorders
Tremor 7
Dizziness 6
Somnolence 4
Hypokinesia 4
Bradykinesia 4
Cogwheel rigidity 3
Dyskinesia 3
Gastrointestinal disorders
Abdominal pain 2
Vascular disorders
Hypertension 3
General disorders and administration site conditions
Fall 12
Application site erythema 11
Application site irritation, pruritus, rash 3; 5; 2
Fatigue 4
Asthenia 2
Gait disturbance 4

Additional adverse reactions observed during the 76-week prospective, open-label study in patients with dementia associated with Parkinson's disease treated with EXELON PATCH: Frequent (those occurring in at least 1/100 patients): dehydration, weight decreased, aggression, hallucination visual.

In patients with dementia associated with Parkinson's disease the following adverse drug reactions have only been observed in clinical trials with EXELON Capsules: Frequent: nausea, vomiting, decreased appetite, restlessness, worsening of Parkinson's disease, bradycardia, diarrhea, dyspepsia, salivary hypersecretion, sweating increased; Infrequent (those occurring between 1/100 to 1/1000 patients): dystonia, atrial fibrillation, atrioventricular block.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of EXELON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypertension, application site hypersensitivity, urticaria, blister, allergic dermatitis, seizure, Parkinson's disease (worsening), tachycardia, abnormal liver function tests, disseminated allergic dermatitis, and tremor.

Read the Exelon Patch (rivastigmine transdermal system) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Metoclopramide

Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and EXELON PATCH is not recommended.

Cholinomimetic And Anticholinergic Medications

EXELON PATCH may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine). Concomitant use of EXELON PATCH with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see WARNINGS AND PRECAUTIONS].

Beta-blockers

Additive bradycardic effects resulting in syncope may occur when EXELON is used concomitantly with betablockers, especially cardioselective beta-blockers (including atenolol). Concomitant use is not recommended when signs of bradycardia including syncope are present.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 11/30/2015

Side Effects
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Exelon Patch - User Reviews

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