1.1       Alzheimer’s Disease

Exelon Patch is indicated for the treatment of mild to moderate dementia of the Alzheimer’s type.

1.2       Parkinson’s Disease Dementia

Exelon Patch is indicated for the treatment of mild to moderate dementia associated with Parkinson’s disease.

2.1       Recommended Dosing

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.

Initial Dose

Initiate treatment with one 4.6 mg/24 hours Exelon Patch 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 well tolerated. Continue the recommended 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. 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)].

Interruption of Treatment

If dosing is interrupted for three days or fewer, restart treatment with the same or lower strength Exelon Patch. If dosing is interrupted for more than three days, restart treatment with the 4.6 mg/24 hours Exelon Patch and titrate as described above.

2.2       Dosing in Specific Populations

Dosing Modifications in Patients with Renal or Hepatic Impairment

Consider using the 4.6 mg/24 hours Exelon Patch as both the initial and maximum dose in patients with moderate to severe renal impairment and in patients with mild to moderate hepatic impairment. Pharmacokinetic studies of oral rivastigmine in these patient populations showed reduced clearance of the drug [see Use in Specific Populations (8.6, 8.7), Clinical Pharmacology (12.3)].  

Dosing Modifications in Patients with Low Body Weight

Because rivastigmine blood levels vary with weight [see Use in Specific Populations (8.8), Clinical Pharmacology (12.3)], carefully titrate and monitor patients with low body weight (<50kg) 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.

2.3       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 <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 6-12 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.

2.4       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 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. If taking 4.6 mg/24 hours, instruct patients to only wear one patch at a time (remove the previous day's patch before applying a new patch) [see Warnings and Precautions (5.1) and Overdosage (10)]. If a dose is missed, apply a new patch immediately.

(e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days. Do not apply a new patch to the same location for at least 14 days.

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

(g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children.

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. [see Dosage and Administration (2.4)].

5.2       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 [see Adverse Reactions (6.1)]. 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 [see Dosage and Administration (2.1)].

If treatment is interrupted for more than three 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 three days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.

5.3       Other Adverse Reactions from Increased Cholinergic Activity

Neurologic Effects

Extrapyramidal Symptoms: Like other cholinomimetics, 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. In clinical trials, rivastigmine was not associated with any increased incidence of cardiovascular adverse events, heart rate or blood pressure changes, or ECG abnormalities. 

Genitourinary Effects

Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.

Pulmonary Effects

Like other drugs that increase cholinergic activity, Exelon Patch should be used with care in patients with a history of asthma or obstructive pulmonary disease.

5.4       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 the Exelon Patch, routinely evaluate the patient's ability to continue driving or operating machinery.

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.

Exelon Patch has been administered to 1634 patients with Alzheimer's disease during clinical trials worldwide. Of these, 1388 patients have been treated for at least 12 weeks, 1182 patients have been treated for at least 24 weeks, and 582 patients have been treated for at least 48 weeks.

24-Week International Placebo-Controlled Trial (Study 1)

Most Commonly Observed Adverse Reactions

The most commonly observed adverse reactions in patients administered Exelon Patch in Study 1 [see Clinical Studies (14.1)], defined as those occurring at a frequency of at least 5% in the 9.5 mg/24 hours Exelon Patch 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 17.4 mg/24 hours Exelon Patch than in those using the 9.5 mg/24 hours Exelon Patch.

Discontinuation Rates

In Study 1, which randomized a total of 1195 patients, the proportions of patients in the Exelon Patch 9.5 mg/24 hours, Exelon capsules 6 mg twice daily, and placebo groups who discontinued treatment due to adverse events were 9.6%, 8.1%, and 5.0%, respectively.

The most common adverse reactions in the Exelon Patch-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 Exelon Patch 9.5 mg/24 hours, Exelon 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 Exelon Patch 9.5 mg/24 hours, Exelon capsules 6 mg twice daily, and placebo groups, respectively.

Adverse Reactions Observed at an Incidence of ≥2%

Table 1 lists adverse reactions seen at an incidence of ≥2% in either Exelon Patch-treated group in Study 1 and for which the rate of occurrence was greater for patients treated with that dose of Exelon Patch than for those treated with placebo. The unapproved 17.4 mg/24 hours Exelon Patch arm is included to demonstrate the increased rates of gastrointestinal adverse reactions over those seen with the 9.5 mg/24 hours Exelon Patch.

*Vomiting was severe in 0% of patients who received Exelon Patch 9.5 mg/24 hours, 1% of patients who received Exelon Patch 17.4 mg/24 hours, 1% of patients who received the Exelon capsule at doses up to 6 mg BID, 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 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 8% of those treated with Exelon Patch 9.5 mg/24 hours, 12% of those treated with Exelon Patch 17.4 mg/24 hours, 11% of patients who received the Exelon capsule at doses up to 6 mg BID 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 Commonly Observed Adverse Reactions

In Study 2 [see Clinical Studies (14.2)] of the commonly observed adverse reactions (≥ 3% in any treatment group) the most frequent event in the Exelon Patch 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 2). The percentage of patients with these events was higher in the Exelon Patch 13.3 mg/24 hours group than in the Exelon Patch 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.

Most Commonly Observed Adverse Reactions ≥3%

Other adverse reactions of interest which occurred less frequently, but which were observed in a markedly higher percentage of patients in the Exelon Patch 13.3 mg/24 hours group than in the Exelon Patch 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 majority of patients reported adverse events of mild to moderate severity. The adverse event severity profile was generally similar for both the Exelon Patch 13.3 mg/24 hours and 9.5 mg/24 hours groups.

Application Site Reactions in the 24-Week and 48-Week Studies (Studies 1 and 2)

A direct comparison of the rates of application site reactions reported in the placebo-controlled and active comparator controlled clinical trials cannot be made due to differences in the method of data collection employed in each of the trials.

In Study 1, cases of skin irritation were captured separately on an investigator-rated skin irritation scale and not as adverse events unless they fulfilled the criteria for a serious adverse event. Skin irritation, when observed, was mostly slight or mild in severity and was rated as severe in ≤2.2% of Exelon Patch patients, versus ≤1.0% of placebo patch patients. Among the skin reactions reported were the following: application site reactions, application site dermatitis and application site irritation.

In Study 2, cases of application site reactions were captured as patient or caregiver reported adverse events. The most commonly reported skin irritation events for both treatment groups were application site erythema and application site pruritus. These events occurred more frequently during the first 24 weeks of the double-blind period and decreased over time in each treatment group after 24 weeks (Table 3). The most common reason for discontinuation due to application site reactions was application site pruritus which occurred in 1.1% of the patients in each treatment group (Table 2). Application site reactions were mostly mild or moderate in severity and were rated as severe in less than 2% of patients.

Other Adverse Events Observed During Clinical Trials

The frequencies represent the proportion of 1634 patients from 2 controlled and 4 open-label trials in North America, Europe, Latin America, Asia and Japan who experienced that event while receiving Exelon Patch. All patch doses are pooled.

All adverse events occurring in approximately 0.1% are included, except for those already listed elsewhere in labeling, too general to be informative, or relatively minor events.

Events are classified by system organ class and listed using the following definitions: Frequent – those occurring in at least 1/100 patients; Infrequent – those occurring in 1/100 to 1/1000 patients. These adverse events are not necessarily related to Exelon Patch treatment and in most cases were observed at a similar frequency in placebo-treated patients in the controlled studies.

Cardiac Disorders: Infrequent: Bradycardia, atrial fibrillation, atrioventricular block, arrhythmia, supraventricular extrasystole.

Ear and Labyrinth Disorders: Infrequent: Tinnitus.

Eye Disorders: Infrequent: Vision blurred.

Gastrointestinal System: Frequent: Constipation, gastritis. Infrequent: Gastroesophageal reflux disease, hematochezia, hematemesis, pancreatitis, salivary hypersecretion.

General Disorders and Administration Site Conditions: Infrequent: Chest pain.

Injury, Poisoning and Procedural Complications: Infrequent: Hip fracture.

Investigations: Infrequent: Blood creatine phosphokinase increased, lipase increased, blood amylase increased, electrocardiogram QT prolonged.

Metabolic and Nutritional Disorders: Frequent: Dehydration. Infrequent: Hypokalemia, hyponatremia.

Nervous System Disorders: Infrequent: Migraine.

Psychiatric Disorders: Infrequent: Delirium

Respiratory, Thoracic, and Mediastinal Disorders: Infrequent: Dyspnea, bronchospasm.

Skin and Subcutaneous Tissue Disorders: Frequent: Pruritus. Infrequent: Erythema, eczema, dermatitis, rash erythematous, skin ulcer.

Vascular Disorders: Infrequent: Hypotension, cerebrovascular accident.

Other Adverse Reactions Observed with Exelon Capsules or Oral Solution

The following additional adverse reactions have been observed with Exelon capsules/oral solution:

         Confusion, abnormal liver function tests, duodenal ulcers, angina pectoris, myocardial infarction, tremor

6.2       Postmarketing Experience

The following additional adverse reactions have been identified based on postmarketing spontaneous reports and are not listed above. 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.

         Hypertension, application site hypersensitivity, urticaria, blister, allergic dermatitis, seizure, worsening of Parkinson’s disease in patients with Parkinson’s disease who were treated with Exelon Patch, tachycardia.

7.1       Cholinomimetic and Anticholinergic Drugs

Rivastigmine may increase the cholinergic effects of other cholinomimetic drugs. Rivastigmine may also interfere with the activity of anticholinergic medications. Avoid concomitant use of rivastigmine with drugs having these pharmacologic effects unless deemed clinically necessary.

8.1       Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. No dermal reproduction studies in animals have been conducted. Oral reproduction studies conducted in pregnant rats and rabbits revealed no evidence of teratogenicity. Studies in rats showed slightly decreased fetal/pup weight, usually at doses causing some maternal toxicity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

8.3       Nursing Mothers

Rivastigmine and its metabolites are excreted in rat milk following oral administration of rivastigmine; levels of rivastigmine plus metabolites in rat milk are approximately two times that in maternal plasma. It is not known whether rivastigmine is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Exelon Patch, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4       Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Use of Exelon Patch in children and adolescents (below 18 years of age) is not recommended.

8.5       Geriatric Use

Of the total number of subjects in clinical studies of Exelon Patch, 88% were 65 and over, while 53% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, 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       Renal Impairment 

In patients with moderate to severe renal impairment (glomerular filtration rate [GFR] <50 mL/min), clearance of oral rivastigmine was reduced [see Clinical Pharmacology (12.3)]. In these patients, consider using the lowest dose Exelon Patch (4.6 mg/24 hours) for both initial and maintenance therapy.

8.7       Hepatic Impairment 

In patients with mild or moderate hepatic impairment (Child-Pugh score 5-9), clearance of oral rivastigmine was reduced [see Clinical Pharmacology (12.3)]. In these patients, consider using the lowest dose Exelon Patch (4.6 mg/24 hours) for both initial and maintenance therapy. No data are available on the use of rivastigmine in patients with severe hepatic impairment.

8.8       Low or High Body Weight

Because rivastigmine blood levels vary with weight [see Clinical Pharmacology (12.3)], careful titration and monitoring should be performed in patients with low or high body weights. In patients with low body weight (<50 kg), monitor closely for toxicities (e.g., excessive nausea, vomiting), and consider reducing the maintenance dose to the 4.6 mg/24 hour Exelon Patch if such toxicities develop.  In patients with body weight >100 kg, consider the use of doses higher than 9.5 mg/24 hours.

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. If this mechanism is correct, 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 Exelon Patch, there is a lag time of 0.5-1 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 10-16 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 60-80% of peak levels.

Exelon Patch 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 (43-49%) for the Exelon Patch formulation as compared with the oral formulations (73-103%).  Fluctuation (between Cmax and Cmin) is less for Exelon Patch than for the oral formulation of rivastigmine.

Figure 2 displays rivastigmine plasma concentrations over 24 hours for the three available patch strengths.

Figure 2: Rivastigmine Plasma Concentrations Following Dermal 24-Hour Patch Application

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

Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch was applied to the upper back, chest, or upper arm. Two other sites (abdomen and thigh) could be used if none of the three other sites is available, but the practitioner should be aware that the rivastigmine plasma exposure associated with these sites was approximately 20-30% lower.

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patients with Alzheimer’s disease with daily dosing.

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 1.4-2.6 hours. It has an apparent volume of distribution in the range of 1.8-2.7 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 (<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 Exelon Patch application versus 3.5 after oral administration, indicating that much less metabolism occurred after dermal treatment. Less NAP226-90 is formed following patch application, presumably because of the lack of presystemic (hepatic first pass) metabolism. Based on in vitro studies, no unique metabolic routes were detected in human skin.

Elimination

Renal excretion of the metabolites is the major route of elimination. Unchanged rivastigmine is found in trace amounts in the urine. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the feces. The apparent elimination half-life in plasma is approximately 3 hours after patch removal. Renal clearance was approximately
2.1-2.8 L/hr.

Renal Impairment

No study was conducted with Exelon Patch in subjects with renal impairment. Following a single 3-mg dose, mean oral clearance of rivastigmine is 64% lower in moderately impaired renal patients (n=8, GFR=10-50 mL/min) than in healthy subjects (n=10, GFR≥60 mL/min); Cl/F=1.7 L/min and 4.8 L/min, respectively. In patients with severe renal impairment (n=8, GFR<10 mL/min), mean oral clearance of rivastigmine is 43% higher than in healthy subjects (n=10, GFR≥60 mL/min); Cl/F=6.9 L/min and 4.8 L/min, respectively. For unexplained reasons, the severely impaired renal patients had a higher clearance of rivastigmine than moderately impaired patients. Despite this finding, consider a reduced dose in patients with moderate to severe renal impairment [see Dosage and Administration (2.3)].

Hepatic Impairment

No pharmacokinetic study was conducted with Exelon Patch in subjects with hepatic impairment. After multiple 6-mg twice daily oral dosing, the mean clearance of rivastigmine was 65% lower in mild (n=7, Child-Pugh score 5-6) and moderate (n=3, Child-Pugh score 7-9) hepatically impaired patients (biopsy proven, liver cirrhosis) than in healthy subjects (n=10).

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 (2.3)].

Age

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with Exelon Patch.

Gender or Race

No specific pharmacokinetic study was conducted to investigate the effect of gender and race on the disposition of Exelon Patch. A population pharmacokinetic analysis of oral rivastigmine indicated that neither gender (n=277 males and 348 females) nor race (n=575 White, 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 Exelon Patch.

Smoking

Population pharmacokinetic analysis showed that nicotine use increased the oral clearance of rivastigmine by 23% (n=75 smokers and 549 nonsmokers).

Drug Interaction Studies

No specific interaction studies have been conducted with Exelon Patch. 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), ß-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 base/kg/day in rats and 1.6 mg base/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 base/kg/day.