RIVASTIGMINE TARTRATE

Rivastigmine tartrate is a reversible cholinesterase inhibitor and is known chemically as (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)ethyl]-phenyl carbamate hydrogen-(2R,3R)-tartrate. Rivastigmine tartrate is commonly referred to in the pharmacological literature as SDZ ENA 713 or ENA 713. It has an empirical formula of C 14 H 22 N 2 O 2 • C 4 H 6 O 6 (hydrogen tartrate salt – hta salt) and a molecular weight of 400.43 (hta salt). Rivastigmine tartrate is a white to off-white, fine crystalline powder that is very soluble in water, soluble in ethanol and acetonitrile, slightly soluble in n-octanol and very slightly soluble in ethyl acetate. The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 3.0. Rivastigmine Tartrate Capsules USP contain rivastigmine tartrate, equivalent to 1.5 mg, 3 mg, 4.5 mg and 6 mg of rivastigmine base for oral administration. Inactive ingredients are hypromellose, magnesium stearate, microcrystalline cellulose, and colloidal silicon dioxide. Each hard-gelatin capsule contains gelatin, titanium dioxide and red and/or yellow iron oxides. Structure

INDICATIONS & USAGE Rivastigmine tartrate capsules, are an acetylcholinesterase inhibitor indicated for treatment of: Mild to moderate dementia of the Alzheimer’s type (1.1) Mild to moderate dementia associated with Parkinson’s disease (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. 1.2 Parkinson’s Disease Dementia Rivastigmine tartrate capsules are indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease.

DOSAGE & ADMINISTRATION Alzheimer’s Disease: Initiate treatment with 1.5 mg twice a day After a minimum of 2 weeks, if tolerated, increase dose to 3 mg twice a day and further to 4.5 mg twice a day and 6 mg twice a day if tolerated with a minimum of 2 weeks at each dose (2.1) Parkinson’s Disease Dementia: Initiate treatment with 1.5 mg twice a day After a minimum of 4 weeks, if tolerated, increase dose to 3 mg twice a day and further to 4.5 mg twice a day and 6 mg twice a day if tolerated with a minimum of 4 weeks at each dose (2.2) Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening. (2.1) Rivastigmine tartrate oral solution and Rivastigmine tartrate capsules may be interchanged at equal doses. (2.3) 2.1 Recommended Dosing Rivastigmine tartrate capsules should be taken with meals in divided doses in the morning and evening. Alzheimer’s Disease The dosage of Rivastigmine tartrate capsules shown to be effective in controlled clinical trials in Alzheimer’s disease is 6 mg to 12 mg per day, administered twice a day (daily doses of 3 mg to 6 mg twice a day). There is evidence from the clinical trials that doses at the higher end of this range may be more beneficial. Initial Dose Initiate treatment with the 1.5 mg twice a day with Rivastigmine tartrate capsules. Dose Titration After a minimum of 2 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 2 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day). Parkinson’s Disease Dementia The dosage of Rivastigmine tartrate capsules shown to be effective in the single controlled clinical trial conducted in dementia associated with Parkinson’s disease is 3 mg to 12 mg per day, administered twice a day (daily doses of 1.5 mg to 6 mg twice a day). Initial Dose Initiate treatment with the 1.5 mg twice a day with Rivastigmine tartrate capsules. Dose Titration After a minimum of 4 weeks and if well tolerated, increase the dose to 3 mg twice a day. Subsequent increases to 4.5 mg twice a day and 6 mg twice a day should be attempted after a minimum of 4 weeks at the previous dose and if well tolerated. The maximum dose is 6 mg twice a day (12 mg per day). Interruption of Treatment If adverse effects (e.g., nausea, vomiting, abdominal pain, loss of appetite) cause intolerance during treatment, the patient should be instructed to discontinue treatment for several doses and then restart at the same or next lower dose level. If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower dose of Rivastigmine tartrate capsules. If dosing is interrupted for more than 3 days, treatment should be restarted with 1.5 mg twice a day and titrated as described above [see Warnings and Precautions (5.1)] . 2.2 Dosing in Specific Populations Dosing Modifications in Patients with Renal or Hepatic Impairment Pharmacokinetic studies of oral rivastigmine in patients with moderate to severe renal impairment (glomerular filtration rate [GFR] <50 mL/min) and mild to moderate hepatic impairment (Child-Pugh score 5 to 9) showed reduced clearance of the drug [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)] . Accordingly, such patients may be able to only tolerate lower doses. No data are available on the use of rivastigmine in patients with severe hepatic impairment. Dosing Modifications in Patients with Low Body Weight Because rivastigmine blood levels vary with body weight [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)] , careful titration and monitoring should be performed in patients with low body weight. In patients with low body weight (less than 50 kg), monitor closely for toxicities (e.g., excessive nausea, vomiting), and consider reducing the dose if such toxicities develop. 2.3 Important Administration Instructions Rivastigmine tartrate oral solution and Rivastigmine tartrate capsules may be interchanged at equal doses.

Rivastigmine tartrate capsules are contraindicated in patients with: known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation [see Description (11)]. a previous history of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing [see Warnings and Precautions (5.2)]. Isolated cases of generalized skin reactions have been described in postmarketing experience [see Adverse Reactions (6.2)]. Known hypersensitivity to rivastigmine, other carbamate derivatives or other components of the formulation (4) History of application site reaction with rivastigmine transdermal patch suggestive of allergic contact dermatitis, in the absence of negative allergy testing (4, 5.2)

The following adverse reactions are described elsewhere in other sections of the prescribing information: · Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.1)]. · Hypersensitivity Reactions of the Skin [see Warnings and Precautions (5.2)]. · Other Adverse Reactions from Increased Cholinergic Activity [see Warnings and Precautions (5.3)]. Most commonly observed adverse reactions (>5% and 2 times greater than placebo): nausea, vomiting, anorexia, dyspepsia, and asthenia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact 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 Commonly Observed 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, anorexia, dyspepsia, and asthenia. Gastrointestinal Adverse Reactions Rivastigmine tartrate 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 1 2 mg/day (n=1,189) Placebo (n=868) Rivastigmine tartrate ≥ 6 to 1 2 mg/day (n=987) Placebo (n=788) Rivastigmine tartrate ≥ 6 to 1 2 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 treatment-emergent signs and symptoms that were reported 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. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis by which to estimate the relative contribution of drug and nondrug factors to the adverse event incidences in the population studied. 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 events 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 ≥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 Sweating Increased 4 1 Syncope 3 2 Body as a Whole Fatigue 9 5 Asthenia 6 2 Malaise 5 2 Weight Decrease** 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 a rivastigmine tartrate 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 -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). **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. ***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. 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 Commonly Observed Adverse Reactions The most common adverse events, 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 18.2% for patients receiving 3 mg to 12 mg per day compared to 11.2% for patients on placebo during the 24-week study. The most frequent adverse events 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 doses of 3 mg to 12 mg per day than for those treated with placebo in the placebo-controlled trial. The prescriber should be aware that these figures cannot be used to predict the frequency of adverse events in the course of usual medical practice when patient characteristics and other factors may differ from those prevailing during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with 1 basis by which to estimate the relative contribution of drug and non-drug factors to the adverse event incidences in the population studied. In general, adverse reactions were less frequent later in the course of treatment. Table 3 Proportion of Adverse Reactions Observed at a Frequency ≥2% and Occurring at Rate Greater than Placebo in Clinical Trials Active-Controlled Placebo-Controlled Study Body System/Adverse Event 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 0 Psychiatric Disorders Anxiety 4 4 1 Insomnia 2 3 2 Restlessness 1 3 2 Skin and Subcutaneous Tissue Disorders Sweating increased 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. Other Adverse Events Observed During Clinical Trials Mild to Moderate Alzheimer’s Disease Treatment-emergent signs and symptoms that occurred during 8 controlled clinical trials and 9 open-label trials in North America, Western Europe, Australia, South Africa, and Japan were recorded as adverse events by the clinical investigators using terminology of their own choosing. To provide an overall estimate of the proportion of individuals having similar types of events, the events were grouped into a smaller number of standardized categories using a modified WHO dictionary, and event frequencies were calculated across all studies. These categories are used in the listing below. The frequencies represent the proportion of 5,297 patients from these trials who experienced that event while receiving rivastigmine tartrate. All adverse events occurring in at least 6 patients (approximately 0.1%) are included, except for those already listed elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused. Events are classified by body system and listed using the following definitions: frequent adverse events–those occurring in at least 1/100 patients; infrequent adverse events–those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to rivastigmine tartrate treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Autonomic Nervous System: Infrequent: Increased saliva. Body as a Whole: Frequent : Allergy, hot flushes. Cardiovascular System: Frequent: Hypotension, postural hypotension. Central and Peripheral Nervous System: Frequent: Abnormal gait, ataxia, paresthesia, convulsions. Infrequent: Dysphonia, hypoesthesia, migraine, nystagmus. Gastrointestinal System: Frequent: Gastritis, constipation, flatulence. Infrequent: Gastric ulcer, gastroesophageal reflux, GI hemorrhage, hernia, melena, rectal hemorrhage, duodenal ulcer, hematemesis, pancreatitis. Hearing and Vestibular Disorders: Frequent: Tinnitus. Heart Rate and Rhythm Disorders: Frequent: Atrial fibrillation, bradycardia, palpitation. Infrequent: AV block, sick sinus syndrome, supraventricular tachycardia, extrasystoles, tachycardia. Liver and Biliary System Disorders: Infrequent: Abnormal hepatic function tests. Metabolic and Nutritional Disorders: Frequent: Dehydration, hypokalemia. Infrequent: Hyponatremia. Musculoskeletal Disorders: Infrequent: Muscle weakness. Myo-, Endo-, Pericardial and Valve Disorders: Frequent: Angina pectoris, myocardial infarction. Psychiatric Disorders: Frequent: Confusion. Infrequent: Apathy, suicide attempt, increased libido, suicidal ideation. Reproductive Disorders (Female and Male): Infrequent: Breast pain. Resistance Mechanism Disorders: Infrequent: Herpes simplex, otitis media. Respiratory System: Infrequent: Bronchospasm. Skin and Appendages: Frequent: Rashes of various kinds (maculopapular, eczema, bullous, exfoliative, psoriaform, erythematous). Infrequent: Urticaria, contact dermatitis. Urinary System Disorders: Frequent: Hematuria. Infrequent: Acute renal failure, dysuria. Vascular (extracardiac) Disorders: Infrequent: Peripheral ischemia, intracranial hemorrhage. Vision Disorders: Frequent : Cataract. Infrequent: Diplopia, glaucoma. White Cell and Resistance Disorders: Infrequent: Lymphadenopathy. Mild to Moderate Parkinson’s Disease Dementia Additional treatment-emergent adverse events in patients with Parkinson’s disease dementia occurring in at least 1 patient (approximately 0.3%) are listed below, excluding events that are already listed above for the dementia of the Alzheimer’s type or elsewhere in labeling, WHO terms too general to be informative, relatively minor events, or events unlikely to be drug-caused. Events are classified by body system and listed using the following definitions: frequent adverse events– those occurring in at least 1/100 patients; infrequent adverse events–those occurring in 1/100 to 1/1,000 patients. These adverse events are not necessarily related to rivastigmine tartrate treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies. Central and Peripheral Nervous System : Frequent: Transient ischemic attack. Gastrointestinal System: Frequent: Dyspepsia. Infrequent: Fecaloma, dysphagia. General Disorders and Administration Site Conditions: Frequent: Chest pain. Liver and Biliary System Disorders: Infrequent: Elevated gamma-glutamyltransferase level. Musculoskeletal Disorders: Frequent: Back pain. Infrequent: Muscle stiffness. Psychiatric Disorders: Frequent: Agitation, depression. Respiratory System: Frequent: Dyspnea. Infrequent: Cough. Urinary System Disorders: Infrequent: Urinary incontinence. Vision Disorders: Infrequent: Blurred vision. 6.2 Postmarketing Experience Voluntary reports of adverse events temporally associated with rivastigmine tartrate that have been received since market introduction that are not listed above, and that may or may not be causally related to the drug include the following: Hepatobiliary Disorders: Hepatitis. Psychiatric Disorders: Aggression. Skin and Appendages: Stevens-Johnson syndrome, disseminated cutaneous hypersensitivity reactions.

Cholinomimetic and anticholinergic drugs: Avoid concomitant use unless clinically necessary. (7.1) 7.1 Cholinomimetic and Anticholinergic Drugs Increased cholinergic effects may be expected when rivastigmine is given with other cholinomimetic drugs. Rivastigmine may also interfere with the activity of anticholinergic medications. Avoid concomitant use of rivastigmine with drugs having these pharmacologic effects unless deemed clinically necessary.