Rivastigmine

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 Amneal Pharmaceuticals at 1-877-835-5472 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 tartrate 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 tartrate capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2%, and 0.3% in the rivastigmine transdermal system 9.5 mg/24 hours, rivastigmine tartrate 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 Tartrate 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* 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** 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 *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 tartrate capsule at doses up to 6 mg twice daily, and 0% of those who received placebo. **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 tartrate 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. 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 Adverse Reactions (ARs) (Greater Than 1% at any dose) Leading to Discontinuation During 48-week Double-Blind 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 Application site pruritus Aggression 1.4 1.1 0.4 0.4 1.1 1.1 0.9 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 Vomiting Fall 12 10 8 5 5 6 10 9 4 4 3 4 4 3 4 2 2 3 Weight decreased* 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 *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. 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 hours (n=355) and rivastigmine transdermal system 4.6 mg/24 hours (n=359), who discontinued treatment due to adverse reactions were 21% and 14%, respectively. The most frequent adverse reaction leading to discontinuation in the 13.3 mg/24 hours treatment group versus the 4.6 mg/24 hours treatment group was agitation (2.8% versus 2.2%), followed by vomiting (2.5% and 1.1%), nausea (1.7% and 1.1%), decreased appetite (1.7% and 0%), aggression (1.1% and 0.3%), fall (1.1% and 0.3%) and syncope (1.1% and 0.3%). Otherwise, all AEs leading to discontinuation were reported in less than 1% 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 system13.3 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 Rivastigmine Transdermal System 13.3 mg/24 hours 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* 7 3 Nausea 6 3 Depression 5 4 Decreased appetite 5 1 Anxiety 5 5 Hallucination 2 5 *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. 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 tartrate 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 patches: 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 transdermal system. 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

4 CONTRAINDICATIONS Rivastigmine transdermal system is contraindicated in patients with: known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation [see Description (11) ] . previous history of application site reactions with rivastigmine transdermal patch suggestive of allergic contact dermatitis [see Warnings and Precautions (5.3) ] . 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 reactions with rivastigmine transdermal patch suggestive of allergic contact dermatitis. ( 4, 6.2 )

11 DESCRIPTION Rivastigmine transdermal system contains rivastigmine, USP, a reversible cholinesterase inhibitor known chemically as (S)- 3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate. It has an empirical formula of C 14 H 22 N 2 O 2 as the base and a molecular weight of 250.34 g/mol (as the base). Rivastigmine, USP is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate. The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27. Rivastigmine transdermal system is a patch for transdermal administration. The patch is a 4-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner (see Figure 1). The release liner is removed and discarded prior to use. Figure 1: Cross Section of the Rivastigmine Transdermal System Layer 1: Backing Film Layer 2: Drug Product (Acrylic) Matrix Layer 3: Adhesive (Silicone) Matrix Layer 4: Release Liner (removed at time of use) Excipients within the formulation include acrylic copolymers, dimethicone, silicone adhesive applied to a pigmented polyethylene polyester backing, and vitamin E. chem structure figure 1

2 DOSAGE AND ADMINISTRATION Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours. (2.1, 2.4) Initial Dose: Initiate treatment with 4.6 mg/24 hours rivastigmine transdermal system. (2.1) Dose Titration (2.1) : After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose. Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours. Mild to Moderate Alzheimer’s Disease and Parkinson’s Disease Dementia: Rivastigmine transdermal system 9.5 mg/24 hours or 13.3 mg/24 hours once daily. (2.1) Severe Alzheimer’s Disease: Rivastigmine transdermal system 13.3 mg/24 hours once daily. (2.1) For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours. (2.1) Consider dose adjustments in patients with (2.2) : Mild-to-moderate hepatic impairment (8.6) Low (less than 50 kg) body weight (8.7) 2.1 Recommended Dosing Initial Dose Initiate treatment with one 4.6 mg/24 hours rivastigmine transdermal system applied to the skin once daily [see Dosage and Administration (2.4) ] . Dose Titration Increase the dose only after a minimum of 4 weeks at the previous dose, and only if the previous dose has been tolerated. For mild-to-moderate AD and PDD patients, continue the effective dose of 9.5 mg/24 hours for as long as therapeutic benefit persists. Patients can then be increased to the maximum effective dose of 13.3 mg/24 hours dose. For patients with severe AD, 13.3 mg/24 hours is the effective dose. Doses higher than 13.3 mg/24 hours confer no appreciable additional benefit, and are associated with an increase in the incidence of adverse reactions [see Warnings and Precautions (5.2) , Adverse Reactions (6.1) ] . Mild-to-Moderate Alzheimer’s Disease and Mild-to-Moderate Parkinson’s Disease Dementia The effective dosage of rivastigmine transdermal system is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours. Severe Alzheimer’s Disease The effective dosage of rivastigmine transdermal system in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours. Interruption of Treatment If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength rivastigmine transdermal system. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours rivastigmine transdermal system and titrate as described above. 2.2 Dosing in Specific Populations Dosing Modifications in Patients with Hepatic Impairment Consider using the 4.6 mg/24 hours rivastigmine transdermal system as both the initial and maintenance dose in patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . Dosing Modifications in Patients with Low Body Weight Carefully titrate and monitor patients with low body weight (less than 50kg) for toxicities (e.g., excessive nausea, vomiting) and consider reducing the maintenance dose to the 4.6 mg/24 hours rivastigmine transdermal system if such toxicities develop. 2.3 Switching to Rivastigmine Transdermal System from Rivastigmine Tartrate Capsules or Rivastigmine Tartrate Oral Solution Patients treated with rivastigmine tartrate capsules or oral solution may be switched to rivastigmine transdermal system as follows: A patient who is on a total daily dose of less than 6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours rivastigmine transdermal system. A patient who is on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 hours rivastigmine transdermal system. Instruct patients or caregivers to apply the first patch on the day following the last oral dose. 2.4 Important Administration Instructions Rivastigmine transdermal system is a patch for transdermal use on intact skin. (a) Do not use the patch if the pouch seal is broken or the patch is cut, damaged, or changed in any way. (b) Apply the rivastigmine transdermal system once a day. Press down firmly for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing. Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient. If sites on the back are not accessible, apply the patch to the upper arm or chest. Do not apply to a skin area where cream, lotion, or powder has recently been applied. (c) Do not apply to skin that is red, irritated, or cut. (d) Replace the rivastigmine transdermal system with a new patch every 24 hours. Instruct patients to only wear 1 patch at a time (remove the previous day’s patch before applying a new patch) [see Warnings and Precautions (5.1) , Overdosage (10) ] . If a patch falls off or if a dose is missed, apply a new patch immediately and then replace this patch the following day at the usual application time. (e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days. Do not apply a new patch to the same location for at least 14 days. (f) May wear the patch during bathing and in hot weather. But avoid long exposure to external heat sources (excessive sunlight, saunas, solariums). (g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children. (h) Wash hands with soap and water after removing the patch. In case of contact with eyes or if the eyes become red after handling the patch, rinse immediately with plenty of water, and seek medical advice if symptoms do not resolve.

1 INDICATIONS AND USAGE Rivastigmine transdermal system is an acetylcholinesterase inhibitor indicated for treatment of: Mild, moderate, and severe dementia of the Alzheimer’s type (AD). (1.1) Mild-to-moderate dementia associated with Parkinson’s disease (PD). (1.2) 1.1 Alzheimer’s Disease Rivastigmine transdermal system is indicated for the treatment of dementia of the Alzheimer’s type (AD). Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease. 1.2 Parkinson’s Disease Dementia Rivastigmine transdermal system is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).

10 OVERDOSAGE Overdose with rivastigmine transdermal system has been reported in the postmarketing setting [see Warnings and Precautions (5.1) ] . Overdoses have occurred from application of more than one patch at one time and not removing the previous day’s patch before applying a new patch. The symptoms reported in these overdose cases are similar to those seen in cases of overdose associated with rivastigmine oral formulations. Because strategies for the management of overdose are continually evolving, it is advisable to contact a Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. As rivastigmine has a plasma half-life of about 3.4 hours after patch administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the patch should be immediately removed and no further patch should be applied for the next 24 hours. As in any case of overdose, general supportive measures should be utilized. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. Atypical responses in blood pressure and heart rate have been reported with other drugs that increase cholinergic activity when co-administered with quaternary anticholinergics such as glycopyrrolate. Additional symptoms associated with rivastigmine overdose are diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, confusional state, hyperhidrosis, hypertension, hallucinations and malaise. Due to the short plasma elimination half-life of rivastigmine after patch administration, dialysis (hemodialysis, peritoneal dialysis, or hemofiltration) would not be clinically indicated in the event of an overdose. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. A fatal outcome has rarely been reported with rivastigmine overdose.

7 DRUG INTERACTIONS Concomitant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended. ( 7.1, 7.2, 7.3 ) 7.1 Metoclopramide Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and rivastigmine transdermal system is not recommended. 7.2 Cholinomimetic and Anticholinergic Medications Rivastigmine transdermal system may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine). Concomitant use of rivastigmine transdermal system with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see Warnings and Precautions (5.4) ] . 7.3 Beta-blockers Additive bradycardic effects resulting in syncope may occur when rivastigmine is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol). Concomitant use is not recommended when signs of bradycardia including syncope are present.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Although the precise mechanism of action of rivastigmine is unknown, it is thought to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. The effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process. 12.2 Pharmacodynamics After a 6-mg oral dose of rivastigmine in humans, anticholinesterase activity is present in cerebrospinal fluid for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing. In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist. 12.3 Pharmacokinetics Absorption After the initial application of rivastigmine transdermal system, there is a lag time of 0.5 to 1 hour in the absorption of rivastigmine. Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (C max ) can also occur later (at 10 to 16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady-state, trough levels are approximately 60% to 80% of peak levels. Rivastigmine transdermal system 9.5 mg/24 hours gave exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day). Inter-subject variability in exposure was lower (43% to 49%) for the rivastigmine transdermal system formulation as compared with the oral formulations (73% to 103%). Fluctuation (between C max and C min ) is less for rivastigmine transdermal system than for the oral formulation of rivastigmine. Figure 2 displays rivastigmine plasma concentrations over 24 hours for the 3 available patch strengths. Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system. Exposure area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the 3 other sites is available, but the practitioner should be aware that the rivastigmine plasma exposure associated with these sites was approximately 20% to 30% lower. There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease with daily dosing. The pharmacokinetic profile of rivastigmine transdermal patches was comparable in patients with Alzheimer’s disease and in patients with dementia associated with Parkinson’s disease. Distribution Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg. Metabolism Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro , this metabolite shows minimal inhibition of acetylcholinesterase (less than 10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. The metabolite-to-parent AUC ∞ ratio was about 0.7 after rivastigmine transdermal system application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin. Elimination Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14 C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1 to 2.8 L/hr. Age Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with rivastigmine transdermal system. Gender and Race No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of rivastigmine transdermal system. A population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, 4 Asian, and 12 Other) affected clearance of the drug. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of rivastigmine transdermal system. Body Weight A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved [see Dosage and Administration (2.2) ] . Renal Impairment No study was conducted with rivastigmine transdermal system in subjects with renal impairment. Based on population analysis, creatinine clearance did not show any clear effect on steady-state concentrations of rivastigmine or its metabolite. Hepatic Impairment No pharmacokinetic study was conducted with rivastigmine transdermal system in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg twice a day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10) [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) ] . Smoking Following oral rivastigmine administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers). Drug Interaction Studies No specific interaction studies have been conducted with rivastigmine transdermal system. Information presented below is from studies with oral rivastigmine. Effect of Rivastigmine on the Metabolism of Other Drugs Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. No pharmacokinetic interaction was observed between rivastigmine taken orally and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. Effect of Other Drugs on the Metabolism of Rivastigmine Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), beta-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15). figure 2

12.1 Mechanism of Action Although the precise mechanism of action of rivastigmine is unknown, it is thought to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. The effect of rivastigmine may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that rivastigmine alters the course of the underlying dementing process.

12.2 Pharmacodynamics After a 6-mg oral dose of rivastigmine in humans, anticholinesterase activity is present in cerebrospinal fluid for about 10 hours, with a maximum inhibition of about 60% 5 hours after dosing. In vitro and in vivo studies demonstrate that the inhibition of cholinesterase by rivastigmine is not affected by the concomitant administration of memantine, an N-methyl-D-aspartate receptor antagonist.

12.3 Pharmacokinetics Absorption After the initial application of rivastigmine transdermal system, there is a lag time of 0.5 to 1 hour in the absorption of rivastigmine. Concentrations then rise slowly typically reaching a maximum after 8 hours, although maximum values (C max ) can also occur later (at 10 to 16 hours). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. At steady-state, trough levels are approximately 60% to 80% of peak levels. Rivastigmine transdermal system 9.5 mg/24 hours gave exposure approximately the same as that provided by an oral dose of 6 mg twice daily (i.e., 12 mg/day). Inter-subject variability in exposure was lower (43% to 49%) for the rivastigmine transdermal system formulation as compared with the oral formulations (73% to 103%). Fluctuation (between C max and C min ) is less for rivastigmine transdermal system than for the oral formulation of rivastigmine. Figure 2 displays rivastigmine plasma concentrations over 24 hours for the 3 available patch strengths. Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application Over a 24-hour dermal application, approximately 50% of the drug content of the patch is released from the system. Exposure area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the 3 other sites is available, but the practitioner should be aware that the rivastigmine plasma exposure associated with these sites was approximately 20% to 30% lower. There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease with daily dosing. The pharmacokinetic profile of rivastigmine transdermal patches was comparable in patients with Alzheimer’s disease and in patients with dementia associated with Parkinson’s disease. Distribution Rivastigmine is weakly bound to plasma proteins (approximately 40%) over the therapeutic range. It readily crosses the blood-brain barrier, reaching CSF peak concentrations in 1.4 to 2.6 hours. It has an apparent volume of distribution in the range of 1.8 to 2.7 L/kg. Metabolism Rivastigmine is extensively metabolized primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite NAP226-90. In vitro , this metabolite shows minimal inhibition of acetylcholinesterase (less than 10%). Based on evidence from in vitro and animal studies, the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. The metabolite-to-parent AUC ∞ ratio was about 0.7 after rivastigmine transdermal system application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin. Elimination Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14 C-rivastigmine, renal elimination was rapid and essentially complete (greater than 90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately 2.1 to 2.8 L/hr. Age Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with rivastigmine transdermal system. Gender and Race No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of rivastigmine transdermal system. A population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 Caucasian, 34 Black, 4 Asian, and 12 Other) affected clearance of the drug. Similar results were seen with analyses of pharmacokinetic data obtained after the administration of rivastigmine transdermal system. Body Weight A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer’s dementia patients. Rivastigmine exposure is higher in subjects with low body weight. Compared to a patient with a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a body weight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg the concentrations would be approximately halved [see Dosage and Administration (2.2) ] . Renal Impairment No study was conducted with rivastigmine transdermal system in subjects with renal impairment. Based on population analysis, creatinine clearance did not show any clear effect on steady-state concentrations of rivastigmine or its metabolite. Hepatic Impairment No pharmacokinetic study was conducted with rivastigmine transdermal system in subjects with hepatic impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine was 60% lower in hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). After multiple 6-mg twice a day oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10) [see Dosage and Administration (2.2) , Use in Specific Populations (8.6) ] . Smoking Following oral rivastigmine administration (up to 12 mg/day) with nicotine use, population pharmacokinetic analysis showed increased oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers). Drug Interaction Studies No specific interaction studies have been conducted with rivastigmine transdermal system. Information presented below is from studies with oral rivastigmine. Effect of Rivastigmine on the Metabolism of Other Drugs Rivastigmine is primarily metabolized through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Based on in vitro studies, no pharmacokinetic drug interactions with drugs metabolized by the following isoenzyme systems are expected: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. No pharmacokinetic interaction was observed between rivastigmine taken orally and digoxin, warfarin, diazepam, or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is not affected by administration of rivastigmine. Effect of Other Drugs on the Metabolism of Rivastigmine Drugs that induce or inhibit CYP450 metabolism are not expected to alter the metabolism of rivastigmine. Population pharmacokinetic analysis with a database of 625 patients showed that the pharmacokinetics of rivastigmine taken orally were not influenced by commonly prescribed medications such as antacids (n=77), antihypertensives (n=72), beta-blockers (n=42), calcium channel blockers (n=75), antidiabetics (n=21), nonsteroidal anti-inflammatory drugs (n=79), estrogens (n=70), salicylate analgesics (n=177), antianginals (n=35) and antihistamines (n=15). figure 2

20181217

14

3 DOSAGE FORMS AND STRENGTHS Rivastigmine transdermal system is available in 3 strengths. Each patch has a light pink colored backing layer labeled as either: Rivastigmine transdermal system, 4.6 mg/24 hours Rivastigmine transdermal system, 9.5 mg/24 hours Rivastigmine transdermal system, 13.3 mg/24 hours Rivastigmine Transdermal System: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours (3)

Rivastigmine Rivastigmine RIVASTIGMINE RIVASTIGMINE TRIMETHYLSILYL TREATED DIMETHICONOL/TRIMETHYLSILOXYSILICATE CROSSPOLYMER (40/60 W/W) DIMETHICONE ALPHA-TOCOPHEROL light pink with red ink Rivastigmine Rivastigmine RIVASTIGMINE RIVASTIGMINE ALPHA-TOCOPHEROL TRIMETHYLSILYL TREATED DIMETHICONOL/TRIMETHYLSILOXYSILICATE CROSSPOLYMER (40/60 W/W) DIMETHICONE light pink with red ink Rivastigmine Rivastigmine RIVASTIGMINE RIVASTIGMINE ALPHA-TOCOPHEROL DIMETHICONE TRIMETHYLSILYL TREATED DIMETHICONOL/TRIMETHYLSILOXYSILICATE CROSSPOLYMER (40/60 W/W) light pink with red ink

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In oral carcinogenicity studies conducted at doses up to 1.1 mg/kg/day in rats and 1.6 mg/kg/day in mice, rivastigmine was not carcinogenic. In a dermal carcinogenicity study conducted at doses up to 0.75 mg base/kg/day in mice, rivastigmine was not carcinogenic. The mean rivastigmine plasma exposure (AUC) at this dose was less than that in humans at the maximum recommended human dose (13.3 mg/24 hours). Mutagenesis Rivastigmine was clastogenic in in vitro chromosomal aberration assays in mammalian cells in the presence, but not the absence, of metabolic activation. Rivastigmine was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro HGPRT assay, and in an in vivo mouse micronucleus test. Impairment of Fertility No fertility or reproduction studies of dermal rivastigmine have been conducted in animals. Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg/kg/day.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In oral carcinogenicity studies conducted at doses up to 1.1 mg/kg/day in rats and 1.6 mg/kg/day in mice, rivastigmine was not carcinogenic. In a dermal carcinogenicity study conducted at doses up to 0.75 mg base/kg/day in mice, rivastigmine was not carcinogenic. The mean rivastigmine plasma exposure (AUC) at this dose was less than that in humans at the maximum recommended human dose (13.3 mg/24 hours). Mutagenesis Rivastigmine was clastogenic in in vitro chromosomal aberration assays in mammalian cells in the presence, but not the absence, of metabolic activation. Rivastigmine was negative in an in vitro bacterial reverse mutation (Ames) assay, an in vitro HGPRT assay, and in an in vivo mouse micronucleus test. Impairment of Fertility No fertility or reproduction studies of dermal rivastigmine have been conducted in animals. Rivastigmine had no effect on fertility or reproductive performance in rats at oral doses up to 1.1 mg/kg/day.

ANDA207308

Rivastigmine

Rivastigmine

65162-749

HUMAN PRESCRIPTION DRUG

TRANSDERMAL

PRINCIPAL DISPLAY PANEL 4.6 pouch

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Importance of Correct Usage Inform patients or caregivers of the importance of applying the correct dose on the correct part of the body. They should be instructed to rotate the application site in order to minimize skin irritation. The same site should not be used within 14 days. The previous day’s patch must be removed before applying a new patch to a different skin location. Rivastigmine transdermal system should be replaced every 24 hours and the time of day should be consistent. It may be helpful for this to be part of a daily routine, such as the daily bath or shower. Only 1 patch should be worn at a time [see Dosage and Administration (2.4) , Warnings and Precautions (5.1) ] . Instruct patients or caregivers to avoid exposure of the patch to external heat sources (excessive sunlight, saunas, solariums) for long periods of time. Instruct patients who have missed a dose to apply a new patch immediately. They may apply the next patch at the usual time the next day. Instruct patients to not apply 2 patches to make up for 1 missed. Inform the patient or caregiver to contact the physician for retitration instructions if treatment has been interrupted. Discarding Used Patches Instruct patients or caregivers to fold the patch in half after use, return the used patch to its original pouch, and discard it out of the reach and sight of children and pets. They should also be informed that drug still remains in the patch after 24-hour usage. They should be instructed to avoid eye contact and to wash their hands after handling the patch. In case of accidental contact with the eyes, or if their eyes become red after handling the patch, they should be instructed to rinse immediately with plenty of water and to seek medical advice if symptoms do not resolve [see Dosage and Administration (2.4) ] . Gastrointestinal Adverse Reactions Inform patients or caregivers of the potential gastrointestinal adverse reactions such as nausea, vomiting, and diarrhea, including the possibility of dehydration due to these symptoms. Explain that rivastigmine transdermal system may affect the patient’s appetite and/or the patient’s weight. Patients and caregivers should be instructed to look for these adverse reactions, in particular when treatment is initiated or the dose is increased. Instruct patients and caregivers to inform a physician if these adverse reactions persist [see Warnings and Precautions (5.2) ] . Skin Reactions Inform patients or caregivers about the potential for allergic contact dermatitis reactions to occur. Patients or caregivers should be instructed to inform a physician 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 [see Warnings and Precautions (5.3) ] . Concomitant Use of Drugs with Cholinergic Action Inform patients or caregivers that while wearing rivastigmine transdermal system, patients should not be taking rivastigmine tartrate capsules or rivastigmine tartrate oral solution or other drugs with cholinergic effects [see Warnings and Precautions (5.4) ] . Pregnancy Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 12-2018-01

Instructions for Use Rivastigmine (riv” a stig’ meen) Transdermal System You will need the following supplies (See Figure A): Rivastigmine transdermal system is supplied in cartons containing 30 patches (see Figure A) Figure A Rivastigmine transdermal system is a thin, light pink colored, plastic patch that sticks to the skin. Each rivastigmine transdermal system is sealed in a pouch that protects it until you are ready to put it on (See Figure A). Only 1 rivastigmine transdermal system should be worn at a time. Do not apply more than 1 rivastigmine transdermal system at a time to the body. Do not open the pouch or remove the rivastigmine transdermal system until you are ready to apply it. Using rivastigmine transdermal system : Step 1. Choose an area to apply the rivastigmine transdermal system (See Figure B). Instructions for Caregivers: Apply rivastigmine transdermal system to the upper or lower back if it is likely that the patient will remove it. If this is not a concern, the rivastigmine transdermal system can be applied instead to the upper arm or chest. Do not apply the rivastigmine transdermal system to areas where it can be rubbed off by tight clothing or belts. Only apply the rivastigmine transdermal system to healthy skin that is clean, dry, hairless, and free of redness, irritation, burns or cuts. Figure B The diagram represents areas on the body where rivastigmine transdermal system may be applied. Only 1 patch should be worn at a time. Do not apply multiple patches to the body. Step 2. Remove the rivastigmine transdermal system from the pouch (See Figure C). Carefully cut the pouch along the dotted line to open and remove the rivastigmine transdermal system. Save the pouch for later use. Figure C Do not cut or fold the rivastigmine transdermal system itself. Step 3. Remove 1 side of the adhesive liner (See Figure D). A protective liner covers the sticky (adhesive) side of the rivastigmine transdermal system. Peel off 1 side of the protective cover. Do not touch the sticky part of the rivastigmine transdermal system with your fingers. Figure D Step 4. Apply the rivastigmine transdermal system to your skin (See Figure E). Apply the sticky (adhesive) side of the rivastigmine transdermal system to your chosen area of skin and then peel off the other side of the protective cover. Figure E Press down on the rivastigmine transdermal system firmly for 30 seconds to make sure that the edges stick to your skin (See Figure F). Figure F Step 5. Wash your hands with soap and water right away. Note: If your rivastigmine transdermal system falls off, select a new area, and repeat Steps 2 to 5 to apply a new rivastigmine transdermal system. Be sure to replace the new rivastigmine transdermal system the next day at the same time as usual. Removing your rivastigmine transdermal system : Step 6. Remove the rivastigmine transdermal system from the skin (See Figure G). Gently pull on 1 edge of the rivastigmine transdermal system to remove it from your skin. Figure G Throwing away the used rivastigmine transdermal system : Step 7. Throw away the used rivastigmine transdermal system (See Figure H). Fold the used rivastigmine transdermal system in half (with the sticky sides together) and put it back into the pouch that you saved. Figure H Throw away the used rivastigmine transdermal system safely and out of the reach of children and pets. Some medicine stays in the patch for 24 hours after you use it and should be folded together (sticky side together) and safely thrown away. Do not try to re-use rivastigmine transdermal systems. Step 8. Wash your hands with soap and water right away. After you remove the rivastigmine transdermal system, if any adhesive remains on your skin, you can use soap and water or an oil-based substance (such as baby oil) to remove the adhesive. Alcohol or other dissolving liquids (such as nail polish remover) should not be used. This Instructions for Use have been approved by the U.S. Food and Drug Administration. Distributed by: Amneal Pharmaceuticals LLC Bridgewater, NJ 08807 Rev. 12-2018-01 Figure A- new figure b Figure C- new figure d figure e figure f figure g Figure H- new

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 tartrate 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 tartrate capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2%, and 0.3% in the rivastigmine transdermal system 9.5 mg/24 hours, rivastigmine tartrate 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 Tartrate 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* 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** 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 *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 tartrate capsule at doses up to 6 mg twice daily, and 0% of those who received placebo. **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 tartrate 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. 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 Adverse Reactions (ARs) (Greater Than 1% at any dose) Leading to Discontinuation During 48-week Double-Blind 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 Application site pruritus Aggression 1.4 1.1 0.4 0.4 1.1 1.1 0.9 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 Vomiting Fall 12 10 8 5 5 6 10 9 4 4 3 4 4 3 4 2 2 3 Weight decreased* 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 *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. 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 hours (n=355) and rivastigmine transdermal system 4.6 mg/24 hours (n=359), who discontinued treatment due to adverse reactions were 21% and 14%, respectively. The most frequent adverse reaction leading to discontinuation in the 13.3 mg/24 hours treatment group versus the 4.6 mg/24 hours treatment group was agitation (2.8% versus 2.2%), followed by vomiting (2.5% and 1.1%), nausea (1.7% and 1.1%), decreased appetite (1.7% and 0%), aggression (1.1% and 0.3%), fall (1.1% and 0.3%) and syncope (1.1% and 0.3%). Otherwise, all AEs leading to discontinuation were reported in less than 1% 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 system13.3 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 Rivastigmine Transdermal System 13.3 mg/24 hours 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* 7 3 Nausea 6 3 Depression 5 4 Decreased appetite 5 1 Anxiety 5 5 Hallucination 2 5 *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. 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 tartrate 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 patches: 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.

8.5 Geriatric Use Of the total number of patients in clinical studies of rivastigmine transdermal system, 88% were 65 years and over, while 55% were 75 years. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. The use of rivastigmine transdermal system in pediatric patients (below 18 years of age) is not recommended.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of rivastigmine transdermal system in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 times the maximum recommended human dose (MRHD) (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of rivastigmine transdermal system in pregnant women. In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 times the maximum recommended human dose (MRHD) (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis. 8.2 Lactation Risk Summary There are no data on the presence of rivastigmine in human milk, the effects on the breastfed infant, or the effects of rivastigmine on milk production. Rivastigmine and its metabolites are excreted in rat milk following oral administration of rivastigmine; levels of rivastigmine plus metabolites in rat milk are approximately 2 times that in maternal plasma. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for rivastigmine and any potential adverse effects on the breastfed infant from rivastigmine or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. The use of rivastigmine transdermal system in pediatric patients (below 18 years of age) is not recommended. 8.5 Geriatric Use Of the total number of patients in clinical studies of rivastigmine transdermal system, 88% were 65 years and over, while 55% were 75 years. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment Increased exposure to rivastigmine was observed in patients with mild or moderate hepatic impairment with oral rivastigmine. Patients with mild or moderate hepatic impairment may be able to only tolerate lower doses [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] . No data are available on the use of rivastigmine in patients with severe hepatic impairment. 8.7 Low or High Body Weight Because rivastigmine blood levels vary with weight, careful titration and monitoring should be performed in patients with low or high body weights [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Rivastigmine Transdermal System: 4.6 mg/24 hours A 5 cm 2 circular patch, consisting of transparent to translucent adhesive layer on light pink colored backing film printed with “Rivastigmine 4.6 mg/24 hours” in red ink, protected by a removable, transparent, overlapping release liner with dimples surrounding the perimeter of the patch. Each patch of 5 cm 2 contains 9 mg rivastigmine base with in vivo release rate of 4.6 mg/24 hours. They are available as follows: Carton of 30 NDC 65162-825-34 Rivastigmine Transdermal System: 9.5 mg/24 hours A 10 cm 2 circular patch, consisting of transparent to translucent adhesive layer on light pink colored backing film printed with “Rivastigmine 9.5 mg/24 hours” in red ink, protected by a removable, transparent, overlapping release liner with dimples surrounding the perimeter of the patch. Each patch of 10 cm 2 contains 18 mg rivastigmine base with in vivo release rate of 9.5 mg/24 hours. They are available as follows: Carton of 30 NDC 65162-826-34 Rivastigmine Transdermal System: 13.3 mg/24 hours A 15 cm 2 circular patch, consisting of transparent to translucent adhesive layer on light pink colored backing film printed with “Rivastigmine 13.3 mg/24 hours” in red ink, protected by a removable, transparent, overlapping release liner with dimples surrounding the perimeter of the patch. Each patch of 15 cm 2 contains 27 mg rivastigmine base with in vivo release rate of 13.3 mg/24 hours. Carton of 30 NDC 65162-749-34 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep rivastigmine transdermal system in the individual sealed pouch until use. Each pouch contains 1 patch. Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.