Rivastigmine Transdermal System

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).

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) and Clinical Pharmacology (12.3) ] . 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 Rivastigmine Transdermal System if such toxicities develop. 2.3 Switching to Rivastigmine Transdermal System from Rivastigmine Capsules or Rivastigmine Oral Solution Patients treated with Rivastigmine 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 for transdermal use on intact skin. (a)…

5 WARNINGS AND PRECAUTIONS 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. ( 5.1 ) Gastrointestinal Adverse Reactions : May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. ( 5.2 ) 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. ( 5.3 ) 5.1 Medication Errors Resulting in Overdose Medication errors with Rivastigmine Transdermal System 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 Rivastigmine Transdermal System [see Dosage and Administration (2.4) ] . 5.2 Gastrointestinal Adverse Reactions Rivastigmine transdermal system can cause gastrointestinal adverse reactions, including significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss. Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes. The incidence and severity of these reactions are dose-related [see Adverse Reactions (6.1) ] . For this reason, initiate treatment with Rivastigmine Transdermal System 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 [see Dosage and Administration (2.1) ] . If treatment is interrupted for more than 3 days because of intolerance, reinitiate Rivastigmine Transdermal System 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. 5.3 Skin Reactions Skin application site reactions may occur with Rivastigmine Transdermal System. These reactions are not in themselves an indication of sensitization. However, use of Rivastigmine Transdermal System 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 [see Contraindications (4) ] . In patients who develop application site reactions to Rivastigmine Transdermal System 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 Transdermal System may not be able to take rivastigmine in any form. There have been isolated postmarketing reports of patients experiencing disseminated…

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 )

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.

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%-4% and 15%-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.

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 Breckenridge Pharmaceutical, Inc. at 1-800-367-3395 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 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 Capsules 6 mg twice daily, and placebo groups, respectively. The proportions of patients who discontinued treatment due to vomiting were 0%, 2.0%, and 0.3% in the Rivastigmine Transdermal System 9.5 mg/24 hours, Rivastigmine 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 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 Vomiting was severe in 0% of patients who received Rivastigmine Transdermal System 9.5 mg/24 hours, 1% of pa…