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).

2.1 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 transdermal system 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 transdermal system 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 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 transdermal system on the day following the last oral dose.

2.4 Important Administration Instructions

Rivastigmine transdermal system is for transdermal use on intact skin.

a)      Do not use the transdermal system if the pouch seal is broken or the transdermal system 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 transdermal system is less likely to be removed by the patient. If sites on the back are not accessible, apply the transdermal system 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 transdermal system every 24 hours. Instruct patients to only wear 1 transdermal system at a time (remove the previous day's transdermal system before applying a new transdermal system) [see Warnings and Precautions (5.1), Overdosage (10)]. If a transdermal system falls off or if a dose is missed, apply a new transdermal system immediately and then replace this transdermal system the following day at the usual application time.

e)       Change the site of transdermal system application daily to minimize potential irritation, although a new transdermal system 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 transdermal system to the same location for at least 14 days.

f)       May wear the transdermal system during bathing and in hot weather. Avoid long exposure to external heat sources (excessive sunlight, saunas, solariums).

g)      Place used transdermal systems 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 transdermal system. In case of contact with eyes or if the eyes become red after handling the transdermal system, rinse immediately with plenty of water, and seek medical advice if symptoms do not resolve.

Rivastigmine transdermal system is available in 3 strengths. Each transdermal system has a beige backing layer labeled as either:

•   Rivastigmine transdermal system 4.6 mg/24 hours, "Rivastigmine Transdermal System 4.6 mg/24 hours"
•   Rivastigmine transdermal system 9.5 mg/24 hours, "Rivastigmine Transdermal System 9.5 mg/24 hours"
•   Rivastigmine transdermal system 13.3 mg/24 hours, "Rivastigmine Transdermal System 13.3 mg/24 hours"

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)].

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 transdermal system when putting on a new one and the use of multiple transdermal systems 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 transdermal system 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 transdermal system 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 allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal). In these cases, treatment should be discontinued [see Contraindications (4)]. Patients and caregivers should be instructed accordingly.

5.4 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 rivastigmine 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 rivastigmine transdermal system 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 rivastigmine transdermal system 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 rivastigmine transdermal system should be used with care in patients with a history of asthma or obstructive pulmonary disease.

5.5 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 rivastigmine transdermal system, routinely evaluate the patient's ability to continue driving or operating machinery.

The following clinically significant 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)]

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

*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 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 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 (Greater Than 1% at any Dose) Leading to Discontinuation During 48-week Double-Blind Treatment Phase in Study 2

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 Adverse Reactions Over Time in the 48-week Double-Blind Treatment Phase (at least 3% in any Treatment Group) in Study 2

*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 system 13.3 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 transdermal system group reported mild events than in the 13.3 mg/24 hours transdermal system 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 Adverse Reactions in the 24-week Double-Blind Treatment Phase (at least 5% in any Treatment Group) in Study 3

*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 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 Adverse Reactions Reported at a Rate Greater Than or Equal to 2% During the Initial 24-Week Period in Study 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 system: 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 capsules, rivastigmine oral solution, or 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, QTc prolongation, torsades de pointes

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.

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.

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risks associated with the use of rivastigmine 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/m2) 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)].

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 (Cmax) 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 Cmax and Cmin) 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 transdermal system strengths.

Figure 2

Rivastigmine Plasma Concentrations Following Dermal 24-Hour Transdermal System Application

Over a 24-hour dermal application, approximately 50% of the drug content of the transdermal system is released from the system.

Exposure area under the plasma concentration-time curve from time zero to infinity (AUC∞) to rivastigmine (and metabolite NAP226-90) was highest when the transdermal system 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 systems 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 transdermal system 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 14C-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 transdermal system 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).

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.