1 INDICATIONS & USAGE Rivastigmine tartrate is an acetylcholinesterase inhibitor indicated for treatment of: • Mild-to-moderate dementia of the Alzheimers type (AD) ( 1.1 ) • Mild-to-moderate dementia associated with Parkinsons disease (PD) ( 1.2 ) 1.1 Alzheimer's Disease Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia of the Alzheimer's type (AD).

1.2 Parkinson's Disease Dementia Rivastigmine tartrate capsules are indicated for the treatment of mild-to-moderate dementia associated with Parkinson's disease (PD).

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 Macleods Pharma USA, Inc., at 1-888-943-3210 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 capsules have 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 tartrate capsules cholinergic effects.

These include nausea, vomiting, anorexia, dyspepsia, and asthenia.

Gastrointestinal Adverse Reactions Rivastigmine tartrate capsules 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 capsules 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 capsules 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 Placebo Rivastigmine tartrate ≥6 to 12 mg/day Placebo Rivastigmine tartrate ≥6 to 12 mg/day Placebo (n=1,189) (n=868) (n=987) (n=788) (n=1,189) (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 capsules 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 Event Rivastigmine tartrate (6 to 12 mg/day) (n=1,189) Placebo (n=868) Percent of Patients with any Adverse Reaction 92 79 Autonomic Nervous System Sweating Increased 4 1 Syncope 3 2 Body as a Whole Fatigue 9 5 Asthenia 6 2 Malaise 5 2 Decreased Weight** 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* 47 12 Vomiting* 31 6 Diarrhea 19 11 Anorexia*** 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 *Nausea and Vomiting: In the controlled clinical trials, 47% of the patients treated with an rivastigmine tartrate capsules dose in the therapeutic range of 6 mg to 12 mg per day (n=1189) developed nausea (compared with 12% in placebo).

A total of 31% of rivastigmine tartrate capsules-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 capsules-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).

**Weight Decreased: In the controlled trials, approximately 26% of women on high doses of rivastigmine tartrate capsules (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.

***Anorexia: In the controlled clinical trials, of the patients treated with an rivastigmine tartrate capsules 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.

Mild-to-Moderate Parkinson's Disease Dementia Rivastigmine tartrate capsules 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 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 capsules 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 eactions 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 0.0% placebo).

Adverse Reactions Observed at an Incidence of at Least 2% Table 3 lists treatment-emergent signs and symptoms that were reported 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 capsules 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) -* 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 *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.

6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of rivastigmine tartrate capsules.

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, application site hypersensitivity (patch), blister, disseminated allergic dermatitis, Stevens-Johnson syndrome, urticaria