Rivastigmine Transdermal System

5 WARNINGS AND PRECAUTIONS Hospitalization and, rarely, death have been reported due to application of multiple patches at same time. Ensure patients or caregivers receive instruction on proper dosing and administration. ( 5.1 ) Gastrointestinal Adverse Reactions : May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. ( 5.2 ) Application site reactions may occur with the patch form of rivastigmine. Discontinue treatment if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal. ( 5.3 ) 5.1 Medication Errors Resulting in Overdose Medication errors with Rivastigmine Transdermal System have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time. Instruct patients and their caregivers on important administration instructions for Rivastigmine Transdermal System [see Dosage and Administration (2.4) ] . 5.2 Gastrointestinal Adverse Reactions Rivastigmine transdermal system can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. The incidence and severity of these reactions are dose-related [see Adverse Reactions (6.1) ] . For this reason, initiate treatment with Rivastigmine Transdermal System at a dose of 4.6 mg/24 hours and titrate to a dose of 9.5 mg/24 hours and then to a dose of 13.3 mg/24 hours, if appropriate [see Dosage and Administration (2.1) ] . If treatment is interrupted for more than 3 days because of intolerance, reinitiate Rivastigmine Transdermal System with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae. A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration after 8 weeks of treatment interruption. Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration. 5.3 Skin Reactions Skin application site reactions may occur with Rivastigmine Transdermal System. These reactions are not in themselves an indication of sensitization. However, use of Rivastigmine Transdermal System may lead to allergic contact dermatitis. Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued [see Contraindications (4) ] . In patients who develop application site reactions to Rivastigmine Transdermal System suggestive of allergic contact dermatitis and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to rivastigmine by exposure to Rivastigmine Transdermal System may not be able to take rivastigmine in any form. There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). In these cases, treatment should be discontinued [see Contraindications (4) ] . Patients and caregivers should be instructed accordingly. 5.4 Other Adverse Reactions from Increased Cholinergic Activity Neurologic Effects Extrapyramidal Symptoms : Cholinomimetics, including rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson's disease who were treated with Rivastigmine Capsules. Seizures : Drugs that increase cholinergic activity are believed to have some potential for causing seizures. However, seizure activity also may be a manifestation of Alzheimer's disease. Peptic Ulcers/Gastrointestinal Bleeding Cholinesterase inhibitors, including rivastigmine, may increase gastric acid secretion due to increased cholinergic activity. Monitor patients using Rivastigmine Transdermal System for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Use with Anesthesia Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Cardiac Conduction Effects Because rivastigmine increases cholinergic activity, use of the Rivastigmine Transdermal System may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. In clinical trials, rivastigmine was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or electrocardiogram (ECG) abnormalities. Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction. Pulmonary Effects Drugs that increase cholinergic activity, including Rivastigmine Transdermal System, should be used with care in patients with a history of asthma or obstructive pulmonary disease 5.5 Impairment in Driving or Use of Machinery Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions. During treatment with the Rivastigmine Transdermal System, routinely evaluate the patient's ability to continue driving or operating machinery.

6 ADVERSE REACTIONS The following adverse reactions are described below and elsewhere in the labeling: Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.2) ] . Skin Reactions [see Warnings and Precautions (5.3) ]. Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions (5.4) ] . Most common adverse reactions (less than 5% and higher than with placebo): Nausea, vomiting, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Rivastigmine Transdermal System 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 Rivastigmine Transdermal System in Study 1 [see Clinical Studies (14) ] , defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours Rivastigmine Transdermal System 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 Rivastigmine Transdermal System than in those using the 9.5 mg/24 hours Rivastigmine Transdermal System. Discontinuation Rates In Study 1, which randomized a total of 1195 patients, the proportions of patients in the Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine 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 Rivastigmine Transdermal System -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 Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine 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 Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine Capsules 6 mg twice daily, and placebo groups, respectively. Adverse Reactions Observed at an Incidence of Greater Than or Equal to 2% Table 1 lists adverse reactions seen at an incidence of greater than or equal to 2% in either Rivastigmine Transdermal System -treated group in Study 1, and for which the rate of occurrence was greater for patients treated with that dose of Rivastigmine Transdermal System than for those treated with placebo. The unapproved 17.4 mg/24 hours Rivastigmine Transdermal System arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours Rivastigmine Transdermal System. Table 1: Proportion of Adverse Reactions (ARs) Observed with a Frequency of Greater Than or Equal to 2% and Occurring at a Rate Greater Than Placebo in Study 1 Rivastigmine Transdermal System 9.5 mg/24 hours Rivastigmine Transdermal System 17.4 mg/24 hours Rivastigmine 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 Vomiting was severe in 0% of patients who received Rivastigmine Transdermal System 9.5 mg/24 hours, 1% of patients who received Rivastigmine Transdermal System 17.4 mg/24 hours, 1% of patients who received the Rivastigmine Capsule at doses up to 6 mg twice daily, and 0% of those who received placebo. 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 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 Rivastigmine Transdermal System 9.5 mg/24 hours, 12% of those treated with Rivastigmine Transdermal System 17.4 mg/24 hours, 11% of patients who received the Rivastigmine 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. 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 48-Week International Active Comparator-Controlled Trial (Study 2) Most Common Adverse Reactions In Study 2 [see Clinical Studies (14) ] of the commonly observed adverse reactions (greater than or equal to 3% in any treatment group), the most frequent event in the Rivastigmine Transdermal System 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 Rivastigmine Transdermal System 13.3 mg/24 hours group than in the Rivastigmine Transdermal System 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 ARs (Greater Than 1% at Any Dose) Leading to Discontinuation During 48-week Double-Blind (DB) Treatment Phase in Study 2 Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 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 Greater Than or Equal to 3% Other adverse reactions of interest which occurred less frequently, but which were observed in a markedly higher percentage of patients in the Rivastigmine Transdermal System 13.3 mg/24 hours group than in the Rivastigmine Transdermal System 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 Rivastigmine Transdermal System 13.3 mg/24 hours and 9.5 mg/24 hours groups. Table 3: Proportion of ARs Over Time in the 48-week DB-Treatment Phase (at Least 3% in any Treatment Group) in Study 2 Cumulative Week 0 to 48 (DB Phase) Week 0 to 24 (DB Phase) Week >24 to 48 (DB Phase) Preferred Term Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 9.5 mg/24 hours Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 9.5 mg/24 hours Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 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 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 Rivastigmine Transdermal System 9.5 mg/24 hours and 18.6% of those treated with Rivastigmine Transdermal System 13.3 mg/24 hours during the 48-week double-blind treatment period. 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 Severe Alzheimer's Disease 24-Week US Controlled Trial (Study 3) Most Commonly Observed Adverse Reactions The most common adverse reactions in patients administered Rivastigmine Transdermal System in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 13.3 mg/24 hours Rivastigmine Transdermal System arm and at a frequency higher than in the 4.6 mg/24 hours Rivastigmine Transdermal System 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 (14) ] , the proportions of patients in the Rivastigmine Transdermal System 13.3 mg/24 hour (n=355) and Rivastigmine Transdermal System 4.6 mg/24 hour (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 less than1% of patients. Most Commonly Observed Adverse Reactions Greater than or Equal to 5% Other adverse reactions of interest which were observed in a higher percentage of patients in the Rivastigmine Transdermal System 13.3 mg/24 hours group than in the Rivastigmine Transdermal System 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 ARs in the 24-week DB-Treatment Phase (at Least 5% in Any Treatment Group) in Study 3 Preferred term Rivastigmine Transdermal System 13.3 mg/24 hours Rivastigmine Transdermal System 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 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 Rivastigmine Transdermal System 4.6 mg/24 hours and 14.1% of those treated with Rivastigmine Transdermal System 13.3 mg/24 hours during the 24-week double-blind treatment. 7 3 Nausea 6 3 Depression 5 4 Decreased appetite 5 1 Anxiety 5 5 Hallucination 2 5 Application Site Reactions Application site skin reactions leading to discontinuation were observed in less than or equal to 2.3% of Rivastigmine Transdermal System 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 less than or equal to 2.2% of Rivastigmine Transdermal System patients in a double-blind controlled study and in less than or equal to 3.7% of Rivastigmine Transdermal System patients in a double-blind controlled study in Japanese patients. Parkinson's Disease Dementia 76-week International Open-Label Trial (Study 4) Rivastigmine Transdermal System 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 Rivastigmine Transdermal System was initiated at 4.6 mg/24 hours and if tolerated the dose was increased after 4 weeks to 9.5 mg/24 hours. Rivastigmine 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 ARs Reported at a Rate Greater Than or Equal to 2% During the Initial 24-Week Period in Study 4 Adverse Drug Reactions Rivastigmine Transdermal System 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 Rivastigmine Transdermal System: 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 rivastigmine 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of rivastigmine. 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. Cardiac Disorders : Tachycardia Hepatobiliary Disorders : Abnormal liver function tests, hepatitis Nervous System Disorders : Parkinson's disease (worsening), seizure, tremor Psychiatric Disorders : nightmares Skin and Subcutaneous Tissue Disorders : Allergic dermatitis, application site hypersensitivity, blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria Vascular Disorders : Hypertension

<table width="90%" ID="Table1"> <caption>Table 1: Proportion of Adverse Reactions (ARs) Observed with a Frequency of Greater Than or Equal to 2% and Occurring at a Rate Greater Than Placebo in Study 1</caption> <col width="30%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="10%" align="center" valign="top"/> <thead> <tr styleCode="Botrule"> <th/> <th>Rivastigmine Transdermal System 9.5 mg/24 hours</th> <th>Rivastigmine Transdermal System 17.4 mg/24 hours</th> <th>Rivastigmine Capsule 6 mg twice daily</th> <th>Placebo</th> </tr> </thead> <tbody> <tr> <td>Total Patients Studied</td> <td>291</td> <td>303</td> <td>294</td> <td>302</td> </tr> <tr styleCode="Botrule"> <td>Total Percentage of Patients with ARs (%)</td> <td>51</td> <td>66</td> <td>63</td> <td>46</td> </tr> <tr> <td>Nausea</td> <td>7</td> <td>21</td> <td>23</td> <td>5</td> </tr> <tr> <td>Vomiting<footnote ID="foot11">Vomiting was severe in 0% of patients who received Rivastigmine Transdermal System 9.5 mg/24 hours, 1% of patients who received Rivastigmine Transdermal System 17.4 mg/24 hours, 1% of patients who received the Rivastigmine Capsule at doses up to 6 mg twice daily, and 0% of those who received placebo.</footnote> </td> <td>6</td> <td>19</td> <td>17</td> <td>3</td> </tr> <tr> <td>Diarrhea</td> <td>6</td> <td>10</td> <td>5</td> <td>3</td> </tr> <tr> <td>Depression</td> <td>4</td> <td>4</td> <td>4</td> <td>1</td> </tr> <tr> <td>Headache</td> <td>3</td> <td>4</td> <td>6</td> <td>2</td> </tr> <tr> <td>Anxiety</td> <td>3</td> <td>3</td> <td>2</td> <td>1</td> </tr> <tr> <td>Anorexia/Decreased Appetite</td> <td>3</td> <td>9</td> <td>9</td> <td>2</td> </tr> <tr> <td>Weight Decreased<footnote ID="foot12">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 Rivastigmine Transdermal System 9.5 mg/24 hours, 12% of those treated with Rivastigmine Transdermal System 17.4 mg/24 hours, 11% of patients who received the Rivastigmine 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.</footnote> </td> <td>3</td> <td>8</td> <td>5</td> <td>1</td> </tr> <tr> <td>Dizziness</td> <td>2</td> <td>7</td> <td>7</td> <td>2</td> </tr> <tr> <td>Abdominal Pain</td> <td>2</td> <td>4</td> <td>1</td> <td>1</td> </tr> <tr> <td>Urinary Tract Infection</td> <td>2</td> <td>2</td> <td>1</td> <td>1</td> </tr> <tr> <td>Asthenia</td> <td>2</td> <td>3</td> <td>6</td> <td>1</td> </tr> <tr> <td>Fatigue</td> <td>2</td> <td>2</td> <td>1</td> <td>1</td> </tr> <tr> <td>Insomnia</td> <td>1</td> <td>4</td> <td>2</td> <td>2</td> </tr> <tr> <td>Abdominal Pain Upper</td> <td>1</td> <td>3</td> <td>2</td> <td>2</td> </tr> <tr> <td>Vertigo</td> <td>0</td> <td>2</td> <td>1</td> <td>1</td> </tr> </tbody> </table>

<table width="90%" ID="Table2"> <caption>Table 2: Proportion of Most Common ARs (Greater Than 1% at Any Dose) Leading to Discontinuation During 48-week Double-Blind (DB) Treatment Phase in Study 2</caption> <col width="50%" align="left" valign="top"/> <col width="18%" align="center" valign="top"/> <col width="18%" align="center" valign="top"/> <col width="14%" align="center" valign="top"/> <thead> <tr> <th/> <th valign="bottom">Rivastigmine Transdermal System 13.3 mg/24 hours</th> <th valign="bottom">Rivastigmine Transdermal System 9.5 mg/24 hours</th> <th valign="bottom">Total</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td>Total Patients Studied</td> <td>280</td> <td>283</td> <td>563</td> </tr> <tr styleCode="Botrule"> <td>Total Percentage of Patients with ARs Leading to Discontinuation (%)</td> <td>9.6</td> <td>12.7</td> <td>11.2</td> </tr> <tr> <td>Vomiting</td> <td>1.4</td> <td>0.4</td> <td>0.9</td> </tr> <tr> <td>Application site pruritus</td> <td>1.1</td> <td>1.1</td> <td>1.1</td> </tr> <tr> <td>Aggression</td> <td>0.4</td> <td>1.1</td> <td>0.7</td> </tr> </tbody> </table>

<table width="90%" ID="Table3"> <caption>Table 3: Proportion of ARs Over Time in the 48-week DB-Treatment Phase (at Least 3% in any Treatment Group) in Study 2</caption> <col width="28%" align="left" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <col width="12%" align="center" valign="bottom"/> <thead> <tr styleCode="Botrule"> <th/> <th styleCode="Rrule" colspan="2">Cumulative Week 0 to 48 (DB Phase)</th> <th styleCode="Rrule" colspan="2">Week 0 to 24 (DB Phase)</th> <th colspan="2">Week &gt;24 to 48 (DB Phase)</th> </tr> <tr> <th valign="bottom">Preferred Term</th> <th valign="bottom">Rivastigmine Transdermal System 13.3 mg/24 hours</th> <th styleCode="Rrule" valign="bottom">Rivastigmine Transdermal System 9.5 mg/24 hours</th> <th valign="bottom">Rivastigmine Transdermal System 13.3 mg/24 hours</th> <th styleCode="Rrule" valign="bottom">Rivastigmine Transdermal System 9.5 mg/24 hours</th> <th valign="bottom">Rivastigmine Transdermal System 13.3 mg/24 hours</th> <th valign="bottom">Rivastigmine Transdermal System 9.5 mg/24 hours</th> </tr> </thead> <tbody> <tr> <td>Total Patients Studied</td> <td>280</td> <td styleCode="Rrule">283</td> <td>280</td> <td styleCode="Rrule">283</td> <td>241</td> <td>246</td> </tr> <tr styleCode="Botrule"> <td>Total Percentage of Patients with ARs (%)</td> <td>75</td> <td styleCode="Rrule">68</td> <td>65</td> <td styleCode="Rrule">55</td> <td>42</td> <td>40</td> </tr> <tr> <td>Nausea</td> <td>12</td> <td styleCode="Rrule">5</td> <td>10</td> <td styleCode="Rrule">4</td> <td>4</td> <td>2</td> </tr> <tr> <td>Vomiting</td> <td>10</td> <td styleCode="Rrule">5</td> <td>9</td> <td styleCode="Rrule">3</td> <td>3</td> <td>2</td> </tr> <tr> <td>Fall</td> <td>8</td> <td styleCode="Rrule">6</td> <td>4</td> <td styleCode="Rrule">4</td> <td>4</td> <td>3</td> </tr> <tr> <td>Weight decreased<footnote ID="foot31">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 Rivastigmine Transdermal System 9.5 mg/24 hours and 18.6% of those treated with Rivastigmine Transdermal System 13.3 mg/24 hours during the 48-week double-blind treatment period.</footnote> </td> <td>7</td> <td styleCode="Rrule">3</td> <td>3</td> <td styleCode="Rrule">1</td> <td>5</td> <td>2</td> </tr> <tr> <td>Application site erythema</td> <td>6</td> <td styleCode="Rrule">6</td> <td>6</td> <td styleCode="Rrule">5</td> <td>1</td> <td>2</td> </tr> <tr> <td>Decreased appetite</td> <td>6</td> <td styleCode="Rrule">3</td> <td>5</td> <td styleCode="Rrule">2</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td>Diarrhea</td> <td>6</td> <td styleCode="Rrule">5</td> <td>5</td> <td styleCode="Rrule">4</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td>Urinary tract infection</td> <td>5</td> <td styleCode="Rrule">4</td> <td>3</td> <td styleCode="Rrule">3</td> <td>3</td> <td>2</td> </tr> <tr> <td>Agitation</td> <td>5</td> <td styleCode="Rrule">5</td> <td>4</td> <td styleCode="Rrule">3</td> <td>1</td> <td>2</td> </tr> <tr> <td>Depression</td> <td>5</td> <td styleCode="Rrule">5</td> <td>3</td> <td styleCode="Rrule">3</td> <td>3</td> <td>2</td> </tr> <tr> <td>Dizziness</td> <td>4</td> <td styleCode="Rrule">1</td> <td>3</td> <td styleCode="Rrule">&lt;1</td> <td>2</td> <td>&lt;1</td> </tr> <tr> <td>Application site pruritus</td> <td>4</td> <td styleCode="Rrule">4</td> <td>4</td> <td styleCode="Rrule">3</td> <td>&lt;1</td> <td>1</td> </tr> <tr> <td>Headache</td> <td>4</td> <td styleCode="Rrule">4</td> <td>4</td> <td styleCode="Rrule">4</td> <td>&lt;1</td> <td>&lt;1</td> </tr> <tr> <td>Insomnia</td> <td>4</td> <td styleCode="Rrule">3</td> <td>2</td> <td styleCode="Rrule">1</td> <td>3</td> <td>2</td> </tr> <tr> <td>Abdominal pain upper</td> <td>4</td> <td styleCode="Rrule">1</td> <td>3</td> <td styleCode="Rrule">1</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td>Anxiety</td> <td>4</td> <td styleCode="Rrule">3</td> <td>2</td> <td styleCode="Rrule">2</td> <td>2</td> <td>1</td> </tr> <tr> <td>Hypertension</td> <td>3</td> <td styleCode="Rrule">3</td> <td>3</td> <td styleCode="Rrule">2</td> <td>1</td> <td>1</td> </tr> <tr> <td>Urinary incontinence</td> <td>3</td> <td styleCode="Rrule">2</td> <td>2</td> <td styleCode="Rrule">1</td> <td>1</td> <td>&lt;1</td> </tr> <tr> <td>Psychomotor hyperactivity</td> <td>3</td> <td styleCode="Rrule">3</td> <td>2</td> <td styleCode="Rrule">3</td> <td>2</td> <td>1</td> </tr> <tr> <td>Aggression</td> <td>2</td> <td styleCode="Rrule">3</td> <td>1</td> <td styleCode="Rrule">3</td> <td>1</td> <td>1</td> </tr> </tbody> </table>