EXELON PATCH (rivastigmine transdermal system) contains rivastigmine, 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 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. EXELON PATCH is for transdermal administration. The patch is a 4-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner . The release liner is removed and discarded prior to use. Figure 1: Cross Section of the EXELON PATCH 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 copolymer, poly (butylmethacrylate, methylmethacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E. rivastigmine chemical structure Figure 1: Cross Section of the EXELON PATCH

EXELON PATCH is an acetylcholinesterase inhibitor indicated for treatment of: • Mild, moderate, and severe dementia of the Alzheimer’s type (AD). • Mild-to-moderate dementia associated with Parkinson’s disease (PD)

Alzheimer’s Disease EXELON PATCH 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

Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).

EXELON PATCH is available in 3 strengths. Each patch has a beige backing layer labeled as either: • EXELON ® PATCH 4.6 mg/24 hours, AMCX • EXELON ® PATCH 9.5 mg/24 hours, BHDI • EXELON ® PATCH 13.3 mg/24 hours, CNFU Patch: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours

• Apply patch on intact skin for a 24-hour period; replace with a new patch every 24 hours. • Initial Dose: Initiate treatment with 4.6 mg/24 hours EXELON PATCH. • Dose Titration: 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: EXELON PATCH 9.5 mg/24 hours or 13.3 mg/24 hours once daily. • Severe Alzheimer’s Disease: EXELON PATCH 13.3 mg/24 hours once daily. • For treatment interruption longer than 3 days, retitrate dosage starting at 4.6 mg per 24 hours. • Consider dose adjustments in patients with: o Mild-to-moderate hepatic impairment o Low (less than 50 kg) body weight 2.1 Recommended Dosing Initial Dose Initiate treatment with one 4.6 mg/24 hours EXELON PATCH applied to the skin once daily . 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 . Mild-to-Moderate Alzheimer’s Disease and Mild-to-Moderate Parkinson’s Disease Dementia The effective dosage of EXELON PATCH 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 EXELON PATCH 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 EXELON PATCH. If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours EXELON PATCH and titrate as described above

Dosing in Specific Populations Dosing Modifications in Patients with Hepatic Impairment Consider using the 4.6 mg/24 hours EXELON PATCH 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 . Dosing Modifications in Patients with Low Body Weight Carefully titrate and monitor patients with low body weight (less than 50 kg) for toxicities (e.g., excessive nausea, vomiting), and consider reducing the maintenance dose to the 4.6 mg/24 hours EXELON PATCH if such toxicities develop

Switching to EXELON PATCH from EXELON Capsules or EXELON Oral Solution Patients treated with EXELON Capsules or Oral Solution may be switched to EXELON PATCH 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 EXELON PATCH. • 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 EXELON PATCH. Instruct patients or caregivers to apply the first patch on the day following the last oral dose

Important Administration Instructions EXELON PATCH is 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 EXELON PATCH 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 EXELON PATCH 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) . 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. 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.

• Hospitalization and, rarely, death have been reported due to application of multiple patches at same time. Ensure patients or caregivers receive instruction on proper dosing and administration. • Gastrointestinal Adverse Reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. • Application-site reactions may occur with the patch form of rivastigmine. Discontinue treatment if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal. 5.1 Medication Errors Resulting in Overdose Medication errors with EXELON PATCH have resulted in serious adverse reactions; some cases have required hospitalization, and rarely, led to death. The majority of medication errors have involved not removing the old patch when putting on a new one and the use of multiple patches at one time. Instruct patients and their caregivers on important administration instructions for EXELON PATCH

Gastrointestinal Adverse Reactions EXELON PATCH can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. The incidence and severity of these reactions are dose-related . For this reason, initiate treatment with EXELON PATCH at a dose of 4.6 mg/24 hours, and titrate to a dose of 9.5 mg/24 hours and then to a dose of 13.3 mg/24 hours, if appropriate . If treatment is interrupted for more than 3 days because of intolerance, reinitiate EXELON PATCH with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae. A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration after 8 weeks of treatment interruption. Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur. It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration

Skin Reactions Skin application-site reactions may occur with EXELON PATCH. These reactions are not in themselves an indication of sensitization. However, use of rivastigmine patch may lead to allergic contact dermatitis. Allergic contact dermatitis should be suspected if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued . In patients who develop application-site reactions to EXELON PATCH, suggestive of allergic contact dermatitis and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision. It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form. There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). In these cases, treatment should be discontinued . Patients and caregivers should be instructed accordingly

Other Adverse Reactions From Increased Cholinergic Activity Neurologic Effects Extrapyramidal Symptoms : Cholinomimetics, including rivastigmine, may exacerbate or induce extrapyramidal symptoms. Worsening of parkinsonian symptoms, particularly tremor, has been observed in patients with dementia associated with Parkinson’s disease who were treated with EXELON Capsules. Seizures : Drugs that increase cholinergic activity are believed to have some potential for causing seizures. However, seizure activity also may be a manifestation of Alzheimer's disease. Peptic Ulcers/Gastrointestinal Bleeding Cholinesterase inhibitors, including rivastigmine, may increase gastric acid secretion due to increased cholinergic activity. Monitor patients using EXELON PATCH for symptoms of active or occult gastrointestinal bleeding, especially those at increased risk for developing ulcers, e.g., those with a history of ulcer disease or those receiving concurrent nonsteroidal anti-inflammatory drugs (NSAIDs). Clinical studies of rivastigmine have shown no significant increase, relative to placebo, in the incidence of either peptic ulcer disease or gastrointestinal bleeding. Use with Anesthesia Rivastigmine, as a cholinesterase inhibitor, is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia. Cardiac Conduction Effects Because rivastigmine increases cholinergic activity, use of the EXELON PATCH may have vagotonic effects on heart rate (e.g., bradycardia). The potential for this action may be particularly important in patients with sick sinus syndrome or other supraventricular cardiac conduction conditions. Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction. Pulmonary Effects Drugs that increase cholinergic activity, including EXELON PATCH, should be used with care in patients with a history of asthma or obstructive pulmonary disease

Impairment in Driving or Use of Machinery Dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. The administration of rivastigmine may also result in adverse reactions that are detrimental to these functions. During treatment with EXELON PATCH, routinely evaluate the patient's ability to continue driving or operating machinery.

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 EXELON PATCH is not recommended

Cholinomimetic and Anticholinergic Medications EXELON PATCH 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 EXELON PATCH with medications having these pharmacologic effects is not recommended unless deemed clinically necessary

Beta-Blockers Additive bradycardic effects resulting in syncope may occur when EXELON 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.