FDA label a2dca76e-b37a-d886-e053-2a95a90a0613

5 WARNINGS AND PRECAUTIONS 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 ( 5.1 ) Discontinue rivastigmine in case of disseminated allergic dermatitis, which may occur after oral or transdermal administration ( 4 , 5.2 ). In patients with suspected allergic contact dermatitis after transdermal rivastigmine use, switch to oral rivastigmine only after negative allergy testing. 5.1 Gastrointestinal Adverse Reactions Rivastigmine tartrate 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, patients should always be started at a dose of 1.5 mg twice a day and titrated to their maintenance dose. If treatment is interrupted for longer than 3 days, treatment should be reinitiated with the lowest daily dose [see Dosage and Administration ( 2.3 )] to reduce the possibility of severe vomiting and its potentially serious sequelae (e.g., there has been one postmarketing report of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment with a 4.5 mg dose 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. 5.2 Allergic Dermatitis There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). Treatment should be discontinued if disseminated allergic dermatitis occurs [see Contraindications ( 4 )]. Patients and caregivers should be instructed accordingly [see Patient Counseling Information ( 17 )]. In patients who develop application site reactions, suggestive of allergic contact dermatitis to rivastigmine tartrate patch 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 patch may not be able to take rivastigmine in any form. 5.3 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 tartrate 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 be expected to increase gastric acid secretion due to increased cholinergic activity. Monitor patients using rivastigmine tartrate 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 rivastigmine 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. Syncopal episodes have been reported in 3% of patients receiving 6 mg to 12 mg per day of rivastigmine tartrate, compared to 2% of placebo patients. 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, should be used with care in patients with a history of asthma or obstructive pulmonary disease. 5.4 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 tartrate, 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 ( 5.1 )]. Allergic Dermatitis [see Warnings and Precautions ( 5.2 )]. Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions ( 5.3 )]. Most common adverse reactions (greater than 5% and 2 times greater than placebo): nausea, vomiting, anorexia, dyspepsia, and asthenia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 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 tartrate has been administered to over 5,297 individuals during clinical trials worldwide. Of these, 4,326 patients have been treated for at least 3 months, 3,407 patients have been treated for at least 6 months, 2,150 patients have been treated for 1 year, 1,250 patients have been treated for 2 years, and 168 patients have been treated for over 3 years. With regard to exposure to the highest dose, 2,809 patients were exposed to doses of 10 mg to 12 mg, 2,615 patients treated for 3 months, 2,328 patients treated for 6 months, 1,378 patients treated for 1 year, 917 patients treated for 2 years, and 129 patients treated for over 3 years. Mild to Moderate Alzheimer’s Disease Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% and twice the placebo rate, are largely predicted by rivastigmine's cholinergic effects. These include nausea, vomiting, anorexia, dyspepsia, and asthenia. Gastrointestinal Adverse Reactions Rivastigmine use is associated with significant nausea, vomiting, and weight loss [see Warnings and Precautions ( 5.1 )]. Discontinuation Rates The rate of discontinuation due to adverse events in controlled clinical trials of rivastigmine tartrate was 15% for patients receiving 6 mg to 12 mg per day compared to 5% for patients on placebo during forced weekly dose titration. While on a maintenance dose, the rates were 6% for patients on rivastigmine tartrate compared to 4% for those on placebo. The most common adverse reactions leading to discontinuation, defined as those occurring in at least 2% of patients and at twice the incidence seen in placebo patients, are shown in Table 1. Table 1 Most Frequent Adverse Reactions Leading to Withdrawal from Clinical Trials during Titration and Maintenance in Patients Receiving 6 mg to 12 mg per day Rivastigmine Tartrate Using a Forced-Dose Titration Study Phase Titration Maintenance Overall Rivastigmine Tartrate ≥6 to 12 mg/day (n=1,189) Placebo (n=868) Rivastigmine Tartrate ≥6 to 12 mg/day (n=987) Placebo (n=788) Rivastigmine Tartrate ≥6 to 12 mg/day (n=1,189) Placebo (n=868) Event/% Discontinuing Nausea 8 <1 1 <1 8 1 Vomiting 4 <1 1 <1 5 <1 Anorexia 2 0 1 <1 3 <1 Dizziness 2 <1 1 <1 2 <1 Adverse Reactions Observed at an Incidence of at Least 2% Table 2 lists adverse reactions that occurred in at least 2% of patients in placebo-controlled trials and for which the rate of occurrence was greater for patients treated with rivastigmine tartrate doses of 6 mg to 12 mg per day than for those treated with placebo. In general, adverse reactions were less frequent later in the course of treatment. No systematic effect of race or age could be determined from the incidence of adverse reactions in the controlled studies. Nausea, vomiting and weight loss were more frequent in women than men. Table 2 Proportion of Adverse Reactions Observed with a Frequency of Greater Than or Equal to 2% and at a Rate Greater than Placebo in Clinical Trials Body System/Adverse Reaction Rivastigmine Tartrate (6 to 12 mg/day) (n=1,189) Placebo (n=868) Percent of Patients with any Adverse Event 92 79 Autonomic Nervous System Increased Sweating 4 1 Syncope 3 2 Body as a Whole Fatigue 9 5 Asthenia 6 2 Malaise 5 2 Decreased Weight Weight Decreased: In the controlled trials, approximately 26% of women on high doses of rivastigmine tartrate (greater than 9 mg per day) had weight loss equal to or greater than 7% of their baseline weight compared to 6% in the placebo-treated patients. About 18% of the males in the high-dose group experienced a similar degree of weight loss compared to 4% in placebo-treated patients. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug. 3 <1 Cardiovascular Disorders, General Hypertension 3 2 Central and Peripheral Nervous System Dizziness 21 11 Headache 17 12 Somnolence 5 3 Tremor 4 1 Gastrointestinal System Nausea Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an rivastigmine tartrate dose in the therapeutic range of 6 mg to 12 mg per day (n=1,189) developed nausea (compared with 12% in placebo). A total of 31% of rivastigmine tartrate-treated patients developed at least 1 episode of vomiting (compared with 6% for placebo). The rate of vomiting was higher during the titration phase (24% versus 3% for placebo) than in the maintenance phase (14% versus 3% for placebo). The rates were higher in women than men. Five percent of patients discontinued for vomiting, compared to less than 1% for patients on placebo. Vomiting was severe in 2% of rivastigmine tartrate-treated patients and was rated as mild or moderate each in 14% of patients. The rate of nausea was higher during the titration phase (43% versus 9% for placebo) than in the maintenance phase (17% versus 4% for placebo). 47 12 Vomiting 31 6 Diarrhea 19 11 Anorexia Anorexia: In the controlled clinical trials, of the patients treated with a rivastigmine tartrate dose of 6 mg to 12 mg per day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time course nor the severity of the anorexia is known. 17 3 Abdominal Pain 13 6 Dyspepsia 9 4 Psychiatric Disorders Insomnia 9 7 Confusion 8 7 Depression 6 4 Anxiety 5 3 Hallucination 4 3 Aggressive Reaction 3 2 Resistance Mechanism Disorders Urinary Tract Infection 7 6 Mild to Moderate Parkinson’s Disease Dementia Rivastigmine tartrate has been administered to 779 individuals during clinical trials worldwide. Of these, 663 patients have been treated for at least 3 months, 476 patients have been treated for at least 6 months, and 313 patients have been treated for 1 year. Most Common Adverse Reactions The most common adverse reactions, defined as those occurring at a frequency of at least 5% and twice the placebo rate, are largely predicted by rivastigmine tartrate's cholinergic effects. These include nausea, vomiting, tremor, anorexia, and dizziness. Discontinuation Rates The rate of discontinuation due to adverse events in the single placebo-controlled trial of rivastigmine tartrate was 18% for patients receiving 3 mg to 12 mg per day compared to 11% for patients on placebo during the 24-week study. The most frequent adverse reactions that led to discontinuation from this study, defined as those occurring in at least 1% of patients receiving rivastigmine tartrate and more frequent than those receiving placebo, were nausea (3.6% rivastigmine tartrate versus 0.6% placebo), vomiting (1.9% rivastigmine tartrate versus 0.6% placebo), and tremor (1.7% rivastigmine tartrate versus 0% placebo). Adverse Reactions Observed at an Incidence of at Least 2% Table 3 lists adverse reactions that occurred in at least 2% of patients in a single placebo-controlled trial and during the first 24 weeks of a 76-week open-label active-controlled trial for which the rate of occurrence was greater for patients treated with rivastigmine tartrate doses of 3 mg to 12 mg per day than for those treated with placebo in the placebo-controlled trial. In general, adverse reactions were less frequent later in the course of treatment. Table 3 Proportion of Adverse Reactions Observed at a Frequency Greater Than or Equal to 2% and Occurring at Rate Greater than Placebo in Clinical Trials Active-Controlled Study Placebo-Controlled Study Body System/Adverse Reaction Rivastigmine Tartrate (3 to 12 mg/day) (n=294) Rivastigmine Tartrate (3 to 12 mg/day) (n=362) Placebo (n=179) Percent of Patients with any Adverse Event 88 84 71 Gastrointestinal Disorders Nausea 38 29 11 Vomiting 13 17 2 Diarrhea 8 7 4 Upper Abdominal Pain 4 4 1 Salivary hypersecretion 2 1 0 General Disorders and Administrative Site Conditions Fall 10 6 6 Fatigue 5 4 3 Asthenia 4 2 1 Metabolism and Nutritional Disorders Anorexia - 6 3 Decreased Appetite 5 8 5 Dehydration 1 2 1 Nervous System Disorders Tremor 23 10 4 Dizziness 8 6 1 Headache 4 4 3 Somnolence 6 4 3 Parkinson’s Disease (worsening) - Parkinson’s disease (worsening) in the active-controlled study was assessed by reported pre-identified adverse events (tremor, cogwheel rigidity, fall), each of them listed with corresponding frequencies. 3 1 Bradykinesia 3 3 2 Dyskinesia 3 1 1 Cogwheel rigidity 3 1 0 Hypokinesia 2 1 0 Parkinsonism - 2 1 Psychiatric Disorders Anxiety 4 4 1 Insomnia 2 3 2 Restlessness 1 3 2 Skin and Subcutaneous Tissue Disorders Increased Sweating 2 2 1 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of rivastigmine tartrate. 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: seizure. Psychiatric Disorders: Aggression, nightmares. Skin and Subcutaneous Tissue Disorders: Allergic dermatitis, blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria.

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0ECFAG"> <caption>Table 1 Most Frequent Adverse Reactions Leading to Withdrawal from Clinical Trials during Titration and Maintenance in Patients Receiving 6 mg to 12 mg per day Rivastigmine Tartrate Using a Forced-Dose Titration</caption> <colgroup> <col width="21%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> </colgroup> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Study Phase</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Titration</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Maintenance</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Overall</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"/> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">&#x2265;6 to 12 mg/day</content> <content styleCode="bold">(n=1,189)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n=868)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">&#x2265;6 to 12 mg/day</content> <content styleCode="bold">(n=987)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n=788)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">&#x2265;6 to 12 mg/day</content> <content styleCode="bold">(n=1,189)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n=868)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Event/% Discontinuing</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0EGQAG"> <caption>Table 2 Proportion of Adverse Reactions Observed with a Frequency of Greater Than or Equal to 2% and at a Rate Greater than Placebo in Clinical Trials</caption> <colgroup> <col width="41%"/> <col width="30%"/> <col width="30%"/> </colgroup> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Body System/Adverse Reaction</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">(6 to 12 mg/day)</content> <content styleCode="bold">(n=1,189)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n=868)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Percent of Patients with any Adverse Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>92</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>79</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Autonomic Nervous System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Increased Sweating</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Syncope</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fatigue</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Malaise</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decreased Weight <footnote ID="_Reffn6976">Weight Decreased: In the controlled trials, approximately 26% of women on high doses of rivastigmine tartrate (greater than 9 mg per day) had weight loss equal to or greater than 7% of their baseline weight compared to 6% in the placebo-treated patients. About 18% of the males in the high-dose group experienced a similar degree of weight loss compared to 4% in placebo-treated patients. It is not clear how much of the weight loss was associated with anorexia, nausea, vomiting, and the diarrhea associated with the drug.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>&lt;1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Cardiovascular Disorders, General</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypertension</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Central and Peripheral Nervous System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal System</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea <footnote ID="_Reffn6977">Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an rivastigmine tartrate dose in the therapeutic range of 6 mg to 12 mg per day (n=1,189) developed nausea (compared with 12% in placebo). A total of 31% of rivastigmine tartrate-treated patients developed at least 1 episode of vomiting (compared with 6% for placebo). The rate of vomiting was higher during the titration phase (24% versus 3% for placebo) than in the maintenance phase (14% versus 3% for placebo). The rates were higher in women than men. Five percent of patients discontinued for vomiting, compared to less than 1% for patients on placebo. Vomiting was severe in 2% of rivastigmine tartrate-treated patients and was rated as mild or moderate each in 14% of patients. The rate of nausea was higher during the titration phase (43% versus 9% for placebo) than in the maintenance phase (17% versus 4% for placebo).</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>47</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting <footnoteRef IDREF="_Reffn6977"/> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>19</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anorexia <footnote ID="_Reffn6978">Anorexia: In the controlled clinical trials, of the patients treated with a rivastigmine tartrate dose of 6 mg to 12 mg per day, 17% developed anorexia compared to 3% of the placebo patients. Neither the time course nor the severity of the anorexia is known.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abdominal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Confusion</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hallucination</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Aggressive Reaction</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Resistance Mechanism Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Urinary Tract Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> </tbody> </table>

<table cellpadding="0pt" cellspacing="0pt" width="100%" ID="_RefID0EYGBG"> <caption>Table 3 Proportion of Adverse Reactions Observed at a Frequency Greater Than or Equal to 2% and Occurring at Rate Greater than Placebo in Clinical Trials</caption> <colgroup> <col width="39%"/> <col width="20%"/> <col width="20%"/> <col width="20%"/> </colgroup> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"/> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Active-Controlled Study</content> </paragraph> </td> <td align="center" colspan="2" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo-Controlled Study</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body System/Adverse Reaction</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">(3 to 12 mg/day)</content> <content styleCode="bold">(n=294)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Rivastigmine Tartrate</content> <content styleCode="bold">(3 to 12 mg/day)</content> <content styleCode="bold">(n=362)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n=179)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Percent of Patients with any Adverse Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>88</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>84</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>71</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>38</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>29</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>17</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Upper Abdominal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Salivary hypersecretion</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">General Disorders and Administrative Site Conditions</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fall</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Fatigue</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolism and Nutritional Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Decreased Appetite</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dehydration</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Parkinson&#x2019;s Disease (worsening)</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>- <footnote ID="_Reffn6975">Parkinson&#x2019;s disease (worsening) in the active-controlled study was assessed by reported pre-identified adverse events (tremor, cogwheel rigidity, fall), each of them listed with corresponding frequencies.</footnote> </paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Bradykinesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dyskinesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Cogwheel rigidity</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Hypokinesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Parkinsonism</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>-</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Psychiatric Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Anxiety</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Restlessness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and Subcutaneous Tissue Disorders</content> </paragraph> </td> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> <td styleCode="Rrule Botrule " valign="top"/> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Increased Sweating</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table>