Exelon Patch

SIDE EFFECTS

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

• Gastrointestinal Adverse Reactions[see WARNINGS AND PRECAUTIONS].
• Skin Reactions [see WARNINGS AND PRECAUTIONS].
• Other Adverse Reactions from Increased Cholinergic Activity [see WARNINGS AND PRECAUTIONS].

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

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

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

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

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

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 entire FDA prescribing information for Exelon Patch (Rivastigmine Transdermal System)