Rivastigmine

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).

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: 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. (2.1) 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 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 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 inta …

3 DOSAGE FORMS AND STRENGTHS Rivastigmine Transdermal System is available as 4.6 mg/24 hours, 9.5 mg/24 hours or 13.3 mg/24 hours of rivastigmine. • Each transdermal system of 5 cm 2 contains 9 mg rivastigmine, USP base with in vivo release rate of 4.6 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 4.6 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. • Each transdermal system of 10 cm 2 contains 18 mg rivastigmine, USP base with in vivo release rate of 9.5 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 9.5 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. • Each transdermal system of 15 cm 2 contains 27 mg rivastigmine, USP base with in vivo release rate of 13.3 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 13.3 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. Transdermal system: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours ( 3 )

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 system 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 system suggestive of allergic contact dermatitis. ( 4 , 6.2 )

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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 Observed With a Frequency of Greater Than or Equal to 2% and Occurring at a Rate Greater Than Placebo in Study 1 Abbreviation: ARs, adverse reactions. Adverse reaction 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 transd …

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 (5.5) ] . 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.

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.

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) ] .

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) ] .

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.

11 DESCRIPTION Rivastigmine transdermal system contains rivastigmine, a reversible cholinesterase inhibitor known chemically as ( S )-3-[1-(Dimethylamino) ethyl]phenyl ethyl(methyl)carbamate. It has a molecular 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 for transdermal administration. The transdermal system is a 4-layer laminate containing the backing layer, drug matrix, adhesive matrix and slit protective release liner (see Figure 1). The release liner is removed and discarded prior to use. Figure 1: Cross Section of the Rivastigmine Transdermal System Excipients within the formulation include acrylic adhesive, dimethicone, poly(butylmethacrylate, methylmethacrylate), silicone adhesive, and flexible polymer backing film printed with brown ink. The brown ink contains acrylic polymers, carbon black, iron oxides (yellow and red), polyethylene wax, polytetrafluoroethylene, polyvinylpyrrolidone, and sodium dioctyl sulfosuccinate. Rivastigmine transdermal systems are packaged with an additional piece of protective film below the system within each pouch. This piece of protective film is removed and discarded at the time of use. Rivastigmine Structural Formula Figure 1: Cross Section of the Rivastigmine Transdermal System

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 transdermal system at one time and not removing the previous day’s transdermal system before applying a new transdermal system. 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 transdermal system administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the transdermal system should be immediately removed and no further transdermal system 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 coadministered 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 transdermal system 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Rivastigmine Transdermal System is available as 4.6 mg/24 hours, 9.5 mg/24 hours or 13.3 mg/24 hours of rivastigmine. Rivastigmine Transdermal System 4.6 mg/24 hours Each transdermal system of 5 cm2 contains 9 mg rivastigmine, USP base with in vivo release rate of 4.6 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 4.6 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. They are available as follows: NDC 0378-9070-93 carton containing 30 transdermal systems Rivastigmine Transdermal System 9.5 mg/24 hours Each transdermal system of 10 cm2 contains 18 mg rivastigmine, USP base with in vivo release rate of 9.5 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 9.5 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. They are available as follows: NDC 0378-9071-93 carton containing 30 transdermal systems Rivastigmine Transdermal System 13.3 mg/24 hours Each transdermal system of 15 cm2 contains 27 mg rivastigmine, USP base with in vivo release rate of 13.3 mg/24 hours. The round transdermal system consists of a peach-colored backing randomly printed with “Rivastigmine 13.3 mg/24 hours” in brown ink, a translucent adhesive layer, and a clear to slightly hazy oversized release liner that is slit and has small dimples surrounding the transdermal system. Each transdermal system also has a clear to slightly hazy oversized underlay and is contained in a square pouch. The pouch is imprinted with lot number and expiration date. They are available as follows: NDC 0378-9072-93 carton containing 30 transdermal systems S tore at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Keep rivastigmine transdermal system in the individual sealed pouch until use. Each pouch contains 1 transdermal system. Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.