Exelon 9.5 MG/Day 24 HR Transdermal Patch
Generic Name: RIVASTIGMINE
Brand Name: Exelon
- Substance Name(s):
- RIVASTIGMINE
DRUG INTERACTIONS
7 Concomitant use with metoclopramide, beta-blockers, or cholinomimetics and anticholinergic medications is not recommended.
( 7.1 , 7.2 , 7.3 ) 7.1 Metoclopramide Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and EXELON PATCH is not recommended.
7.2 Cholinomimetic and Anticholinergic Medications EXELON PATCH may increase the cholinergic effects of other cholinomimetic medications and may also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine).
Concomitant use of EXELON PATCH with medications having these pharmacologic effects is not recommended unless deemed clinically necessary [see Warnings and Precautions (5.4)] .
7.3 Beta-blockers Additive bradycardic effects resulting in syncope may occur when EXELON is used concomitantly with beta-blockers, especially cardioselective beta-blockers (including atenolol).
Concomitant use is not recommended when signs of bradycardia, including syncope are present.
OVERDOSAGE
10 Overdose with EXELON PATCH has been reported in the postmarketing setting [see Warnings and Precautions (5.1)] .
Overdoses have occurred from application of more than one patch at one time and not removing the previous day’s patch before applying a new patch.
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 patch administration and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose the patch should be immediately removed and no further patch 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 patch 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.
DESCRIPTION
11 EXELON PATCH (rivastigmine transdermal system) contains rivastigmine, a reversible cholinesterase inhibitor known chemically as (S)-3-[1-(dimethylamino) ethyl]phenyl ethylmethylcarbamate.
It has an empirical formula of C 14 H 22 N 2 O 2 as the base and a molecular weight of 250.34 g/mol (as the base).
Rivastigmine is a viscous, clear, and colorless to yellow to very slightly brown liquid that is sparingly soluble in water and very soluble in ethanol, acetonitrile, n-octanol and ethyl acetate.
The distribution coefficient at 37°C in n-octanol/phosphate buffer solution pH 7 is 4.27.
EXELON PATCH is for transdermal administration.
The patch is a 4-layer laminate containing the backing layer, drug matrix, adhesive matrix and overlapping release liner (see Figure 1).
The release liner is removed and discarded prior to use.
Figure 1: Cross Section of the EXELON PATCH Layer 1: Backing Film Layer 2: Drug Product (Acrylic) Matrix Layer 3: Adhesive (Silicone) Matrix Layer 4: Release Liner (removed at time of use) Excipients within the formulation include acrylic copolymer, poly (butylmethacrylate, methylmethacrylate), silicone adhesive applied to a flexible polymer backing film, silicone oil, and vitamin E.
rivastigmine chemical structure Figure 1: Cross Section of the EXELON PATCH
CLINICAL STUDIES
14 The effectiveness of the EXELON PATCH in dementia of the Alzheimer’s type and dementia associated with Parkinson’s disease was based on the results of 3 controlled trials of EXELON PATCH in patients with Alzheimer’s disease (Studies 1, 2, and 3) (see below); 3 controlled trials of oral rivastigmine in patients with dementia of the Alzheimer’s type; and 1 controlled trial of oral rivastigmine in patients with dementia associated with Parkinson’s disease.
See the prescribing information for oral rivastigmine for details of the four studies of oral rivastigmine.
Mild-to-Moderate Alzheimer’s Disease International 24-Week Study of EXELON PATCH in Dementia of the Alzheimer’s Type (Study 1) This study was a randomized double-blind, double dummy clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental Status Examination (MMSE) score greater than or equal to 10 and less than or equal to 20] (Study 1).
The mean age of patients participating in this trial was 74 years with a range of 50 to 90 years.
Approximately 67% of patients were women, and 33% were men.
The racial distribution was Caucasian 75%, black 1%, Asian 9%, and other races 15%.
The effectiveness of the EXELON PATCH was evaluated in Study 1 using a dual outcome assessment strategy, evaluating for changes in both cognitive performance and overall clinical effect.
The ability of the EXELON PATCH to improve cognitive performance was assessed with the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog), a multi-item instrument that has been extensively validated in longitudinal cohorts of Alzheimer’s-disease patients.
The ADAS-Cog examines selected aspects of cognitive performance, including elements of memory, orientation, attention, reasoning, language, and praxis.
The ADAS-Cog scoring range is from 0 to 70, with higher scores indicating greater cognitive impairment.
Elderly normal adults may score as low as 0 or 1, but it is not unusual for non-demented adults to score slightly higher.
The ability of the EXELON PATCH to produce an overall clinical effect was assessed using the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC).
The ADCS-CGIC is a more standardized form of the Clinician’s Interview-Based Impression of Change-Plus (CIBIC-Plus) and is also scored as a 7-point categorical rating; scores range from 1, indicating “markedly improved,” to 4, indicating “no change,” to 7, indicating “marked worsening.” In Study 1, 1195 patients were randomized to 1 of the following 4 treatments: EXELON PATCH 9.5 mg/24 hours, EXELON PATCH 17.4 mg/24 hours, EXELON Capsules in a dose of 6 mg twice daily, or placebo.
This 24-week study was divided into a 16-week titration phase followed by an 8-week maintenance phase.
In the active treatment arms of this study, doses below the target dose were permitted during the maintenance phase in the event of poor tolerability.
Figure 3 illustrates the time course for the change from baseline in ADAS-Cog scores for all 4 treatment groups over the 24-week study.
At 24 weeks, the mean differences in the ADAS-Cog change scores for the EXELON-treated patients compared to the patients on placebo, were 1.8, 2.9, and 1.8 units for the EXELON PATCH 9.5 mg/24 hours, EXELON PATCH 17.4 mg/24 hours, and EXELON Capsule 6 mg twice daily groups, respectively.
The difference between each of these groups and placebo was statistically significant.
Although a slight improvement was observed with the 17.4 mg/24 hours patch compared to the 9.5 mg/24 hours patch on this outcome measure, no meaningful difference between the two was seen on the global evaluation (see Figure 4).
Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 1 Figure 4 presents the distribution of patients’ scores on the ADCS-CGIC for all 4 treatment groups.
At 24 weeks, the mean difference in the ADCS-CGIC scores for the comparison of patients in each of the EXELON-treated groups with the patients on placebo was 0.2 units.
The difference between each of these groups and placebo was statistically significant.
Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing Study 1 International 48-Week Study of EXELON PATCH in Dementia of the Alzheimer’s Type (Study 2) This study was a randomized double-blind clinical investigation in patients with Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 10 and less than or equal to 24] (Study 2).
The mean age of patients participating in this trial was 76 years with a range of 50 to 85 years.
Approximately 65% of patients were women and 35% were men.
The racial distribution was approximately Caucasian 97%, black 2%, Asian 0.5%, and other races 1%.
Approximately 27% of the patients were taking memantine throughout the entire duration of the study.
Alzheimer’s disease patients who received 24 to 48 weeks open-label treatment with EXELON PATCH 9.5 mg/24 hours and who demonstrated functional and cognitive decline were randomized into treatment with either EXELON PATCH 9.5 mg/24 hours or EXELON PATCH 13.3 mg/24 hours in a 48-week, double-blind treatment phase.
Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of greater than or equal to 2 points from the previous visit or a decrease of greater than or equal to 3 points from baseline.
Study 2 was designed to compare the efficacy of EXELON PATCH 13.3 mg/24 hours versus that of EXELON PATCH 9.5 mg/24 hours during the 48-week, double-blind treatment phase.
The ability of the EXELON PATCH 13.3 mg/24 hours to improve cognitive performance over that provided by the EXELON PATCH 9.5 mg/24 hours was assessed by the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) [see Clinical Studies (14)] .
The ability of the EXELON PATCH 13.3 mg/24 hours to improve overall function versus that provided by EXELON PATCH 9.5 mg/24 hours was assessed by the instrumental subscale of the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-IADL).
The ADCS-IADL subscale is composed of items 7 to 23 of the caregiver-based ADCS-ADL scale.
The ADCS-IADL assesses activities, such as those necessary for communicating and interacting with other people, maintaining a household, and conducting hobbies and interests.
A sum score is calculated by adding the scores of the individual items and can range from 0 to 56, with higher scores indicating less impairment.
Out of a total of 1584 patients enrolled in the initial open-label phase of the study, 567 patients were classified as decliners and were randomized into the 48-week double-blind treatment phase of the study.
Two hundred eighty-seven (287) patients entered the 9.5 mg/24 hours EXELON PATCH treatment group and 280 patients entered the 13.3 mg/24 hours EXELON PATCH treatment group.
Figure 5 illustrates the time course for the mean change from double-blind baseline in ADCS-IADL scores for each treatment group over the course of the 48-week treatment phase of the study.
Decline in the mean ADCS-IADL score from the double-blind baseline for the Intent to Treat–Last Observation Carried Forward (ITT-LOCF) analysis was less at each timepoint in the 13.3 mg/24 hour EXELON PATCH treatment group than in the 9.5 mg/24 hours EXELON PATCH treatment group.
The 13.3 mg/24 hours dose was statistically significantly superior to the 9.5mg/24 hours dose at weeks 16, 24, 32, and 48 (primary endpoint).
Figure 6 illustrates the time course for the mean change from double-blind baseline in ADAS-Cog scores for both treatment groups over the 48-week treatment phase.
The between-treatment group difference for EXELON PATCH 13.3 mg/24 hours versus EXELON PATCH 9.5 mg/24 hours was nominally statistically significant at week 24 (p = 0.027), but not at week 48 (p = 0.227), which was the primary endpoint.
Figure 5: Time Course of the Change From Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6: Time Course of the Change From Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2 Severe Alzheimer’s Disease 24-Week United States Study With EXELON PATCH in Severe Alzheimer’s Disease (Study 3) This was a 24-week randomized double-blind, clinical investigation in patients with severe Alzheimer’s disease [diagnosed by NINCDS-ADRDA and DSM-IV criteria, Mini-Mental State Examination (MMSE) score greater than or equal to 3 and less than or equal to 12].
The mean age of patients participating in this trial was 78 years with a range of 51 to 96 years with 62% aged greater than 75 years.
Approximately 65% of patients were women and 35% were men.
The racial distribution was approximately Caucasian 87%, black 7%, Asian 1%, and other races 5%.
Patients on a stable dose of memantine were permitted to enter the study.
Approximately 61% of the patients in each treatment group were taking memantine throughout the entire duration of the study.
The study was designed to compare the efficacy of EXELON PATCH 13.3 mg/24 hours versus that of EXELON PATCH 4.6 mg/24 hours during the 24-week double-blind treatment phase.
The ability of the 13.3 mg/24 hours EXELON PATCH to improve cognitive performance versus that provided by the 4.6 mg/24 hours EXELON PATCH was assessed with the Severe Impairment Battery (SIB) which uses a validated 40-item scale developed for the evaluation of the severity of cognitive dysfunction in more advanced AD patients.
The domains assessed included social interaction, memory, language, attention, orientation, praxis, visuospatial ability, construction, and orienting to name.
The SIB was scored from 0 to 100, with higher scores reflecting higher levels of cognitive ability.
The ability of the 13.3 mg/24 hours EXELON PATCH to improve overall function versus that provided by the 4.6 mg/24 hours EXELON PATCH was assessed with the Alzheimer’s Disease Cooperative Study-Activities of Daily Living-Severe Impairment Version (ADCS-ADL-SIV) which is a caregiver-based ADL scale composed of 19 items developed for use in clinical studies of dementia.
It is designed to assess the patient’s performance of both basic and instrumental activities of daily living, such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests, and making judgments and decisions.
A sum score is calculated by adding the scores of the individual items and can range from 0 to 54, with higher scores indicating less functional impairment.
In this study, 716 patients were randomized into one of the following treatments: EXELON PATCH 13.3 mg/24 hours or EXELON PATCH 4.6 mg/24 hours in a 1:1 ratio.
This 24-week study was divided into an 8-week titration phase followed by a 16-week maintenance phase.
In the active treatment arms of this study, temporary dose adjustments below the target dose were permitted during the titration and maintenance phase in the event of poor tolerability.
Figure 7 illustrates the time course for the mean change from baseline SIB scores for each treatment group over the course of the 24-week treatment phase of the study.
Decline in the mean SIB score from the baseline for the Modified Full Analysis Set (MFAS)-Last Observation Carried Forward (LOCF) analysis was less at each timepoint in the 13.3 mg/24 hours EXELON PATCH treatment group than in the 4.6 mg/24 hours EXELON PATCH treatment group.
The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).
Figure 8 illustrates the time course for the mean change from baseline in ADCS-ADL-SIV scores for each treatment group over the course of the 24-week treatment phase of the study.
Decline in the mean ADCS-ADL-SIV score from baseline for the MFAS-LOCF analysis was less at each timepoint in the 13.3 mg/24 hours EXELON PATCH treatment group than in the 4.6 mg/24 hours EXELON PATCH treatment group.
The 13.3 mg/24 hours dose was statistically significantly superior to the 4.6 mg/24 hours dose at weeks 16 and 24 (primary endpoint).
Figure 7: Time Course of the Change From Baseline in SIB Score for Patients Observed at Each Time Point (Modified Full Analysis Set-LOCF) Figure 8: Time Course of the Change From Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified Full Analysis Set-LOCF) Figure 3: Time Course of the Change from Baseline in ADAS-Cog Score for Patients Observed at Each Time Point Figure 4: Distribution of ADCS-CGIC Scores for Patients Completing the Study Figure 5 Time Course of the Change from Double-Blind Baseline in ADCS-IADL Score for Patients Observed at Each Time Point in Study 2 Figure 6 Time Course of the Change from Double-Blind Baseline in ADAS-Cog Score for Patients Observed at Each Time Point in Study 2 Figure 7 Time Course of the Change from Baseline in SIB Score for Patients Observed at Each Time Point (Modified full analysis set–LOCF) Figure 8 Time Course of the Change from Baseline in ADCS-ADL-SIV Score for Patients Observed at Each Time Point (Modified full analysis set – LOCF)
HOW SUPPLIED
16 /STORAGE AND HANDLING EXELON PATCH: 4.6 mg/24 hours Each patch of 5 cm 2 contains 9 mg rivastigmine base with in vivo release rate of 4.6 mg/24 hours.
Carton of 30………………………NDC 0078-0501-15 EXELON PATCH: 9.5 mg/24 hours Each patch of 10 cm 2 contains 18 mg rivastigmine base with in vivo release rate of 9.5 mg/24 hours.
Carton of 30………………………..NDC 0078-0502-15 EXELON PATCH: 13.3 mg/24 hours Each patch of 15 cm 2 contains 27 mg rivastigmine base with in vivo release rate of 13.3 mg/24 hours.
Carton of 30………………………NDC 0078-0503-15 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].
Keep EXELON PATCH in the individual sealed pouch until use.
Each pouch contains 1 patch.
Used systems should be folded, with the adhesive surfaces pressed together, and discarded safely.
GERIATRIC USE
8.5 Geriatric Use Of the total number of patients in clinical studies of EXELON PATCH, 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.
DOSAGE FORMS AND STRENGTHS
3 EXELON PATCH is available in 3 strengths.
Each patch has a beige backing layer labeled as either: EXELON ® PATCH 4.6 mg/24 hours, AMCX EXELON ® PATCH 9.5 mg/24 hours, BHDI EXELON ® PATCH 13.3 mg/24 hours, CNFU Patch: 4.6 mg/24 hours or 9.5 mg/24 hours or 13.3 mg/24 hours ( 3 )
MECHANISM OF ACTION
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.
INDICATIONS AND USAGE
1 EXELON PATCH 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 EXELON PATCH is indicated for the treatment of dementia of the Alzheimer’s type (AD).
Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer’s disease.
1.2 Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).
PEDIATRIC USE
8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.
The use of EXELON PATCH in pediatric patients (below 18 years of age) is not recommended.
PREGNANCY
8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of EXELON in pregnant women.
In animals, no adverse effects on embryo-fetal development were observed at oral doses 2-4 times the maximum recommended human dose (MRHD) (see Data) .
The background risk of major birth defects and miscarriage for the indicated population is unknown.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.
Data Animal Data Oral administration of rivastigmine to pregnant rats and rabbits throughout organogenesis produced no adverse effects on embryo-fetal development up to the highest dose tested (2.3 mg/kg/day), which is 2 and 4 times, respectively, the MRHD of 12 mg per day on a body surface area (mg/m 2 ) basis.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Hospitalization and, rarely, death have been reported due to application of multiple patches at same time.
Ensure patients or caregivers receive instruction on proper dosing and administration.
( 5.1 ) Gastrointestinal Adverse Reactions: May include significant nausea, vomiting, diarrhea, anorexia/decreased appetite, and weight loss, and may necessitate treatment interruption.
Dehydration may result from prolonged vomiting or diarrhea and can be associated with serious outcomes.
( 5.2 ) Application-site reactions may occur with the patch form of rivastigmine.
Discontinue treatment if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.
( 5.3 ) 5.1 Medication Errors Resulting in Overdose Medication errors with 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 3 days because of intolerance, reinitiate EXELON PATCH with the 4.6 mg/24 hours dose to reduce the possibility of severe vomiting and its potentially serious sequelae.
A postmarketing report described a case of severe vomiting with esophageal rupture following inappropriate reinitiation of treatment of an oral formulation of rivastigmine without retitration after 8 weeks of treatment interruption.
Inform caregivers to monitor for gastrointestinal adverse reactions and to inform the physician if they occur.
It is critical to inform caregivers that if therapy has been interrupted for more than 3 days because of intolerance, the next dose should not be administered without contacting the physician regarding proper retitration.
5.3 Skin Reactions Skin application-site reactions may occur with EXELON PATCH.
These reactions are not in themselves an indication of sensitization.
However, use of rivastigmine patch may lead to allergic contact dermatitis.
Allergic contact dermatitis should be suspected if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles), and if symptoms do not significantly improve within 48 hours after patch removal.
In these cases, treatment should be discontinued [see Contraindications (4)] .
In patients who develop application-site reactions to EXELON PATCH, suggestive of allergic contact dermatitis and who still require rivastigmine, treatment should be switched to oral rivastigmine only after negative allergy testing and under close medical supervision.
It is possible that some patients sensitized to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in any form.
There have been isolated postmarketing reports of patients experiencing disseminated allergic dermatitis when administered rivastigmine irrespective of the route of administration (oral or transdermal).
In these cases, treatment should be discontinued [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 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 electrocardiogram (ECG) abnormalities.
Genitourinary Effects Although not observed in clinical trials of rivastigmine, drugs that increase cholinergic activity may cause urinary obstruction.
Pulmonary Effects Drugs that increase cholinergic activity, including EXELON PATCH, should be used with care in patients with a history of asthma or obstructive pulmonary disease.
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 EXELON PATCH, routinely evaluate the patient’s ability to continue driving or operating machinery.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
Importance of Correct Usage Inform patients or caregivers of the importance of applying the correct dose on the correct part of the body.
They should be instructed to rotate the application site in order to minimize skin irritation.
The same site should not be used within 14 days.
The previous day’s patch must be removed before applying a new patch to a different skin location.
EXELON PATCH should be replaced every 24 hours and the time of day should be consistent.
It may be helpful for this to be part of a daily routine, such as the daily bath or shower.
Only 1 patch should be worn at a time [see Dosage and Administration (2.4), Warnings and Precautions (5.1)] .
Instruct patients or caregivers to avoid exposure of the patch to external heat sources (excessive sunlight, saunas, solariums) for long periods of time.
Instruct patients who have missed a dose to apply a new patch immediately.
They may apply the next patch at the usual time the next day.
Instruct patients to not apply 2 patches to make up for 1 missed.
Inform the patient or caregiver to contact the physician for retitration instructions if treatment has been interrupted.
Discarding Used Patches Instruct patients or caregivers to fold the patch in half after use, return the used patch to its original pouch, and discard it out of the reach and sight of children and pets.
They should also be informed that drug still remains in the patch after 24-hour usage.
They should be instructed to avoid eye contact and to wash their hands after handling the patch.
In case of accidental contact with the eyes, or if their eyes become red after handling the patch, they should be instructed to rinse immediately with plenty of water and to seek medical advice if symptoms do not resolve [see Dosage and Administration (2.4)] .
Gastrointestinal Adverse Reactions Inform patients or caregivers of the potential gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, including the possibility of dehydration due to these symptoms.
Explain that EXELON PATCH may affect the patient’s appetite and/or the patient’s weight.
Patients and caregivers should be instructed to look for these adverse reactions, in particular when treatment is initiated or the dose is increased.
Instruct patients and caregivers to inform a physician if these adverse reactions persist [see Warnings and Precautions (5.2)] .
Skin Reactions Inform patients or caregivers about the potential for allergic contact dermatitis reactions to occur.
Patients or caregivers should be instructed to inform a physician if application-site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g., increasing erythema, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal [see Warnings and Precautions (5.3)] .
Concomitant Use of Drugs With Cholinergic Action Inform patients or caregivers that while wearing EXELON PATCH, patients should not be taking EXELON Capsules or EXELON Oral Solution or other drugs with cholinergic effects [see Warnings and Precautions (5.4)] .
Pregnancy Advise patients to notify their healthcare provider if they are pregnant or plan to become pregnant.
Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 T2020-95
DOSAGE AND ADMINISTRATION
2 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 EXELON PATCH.
( 2.1 ) Dose Titration ( 2.1 ): After a minimum of 4 weeks, if tolerated, increase dose to 9.5 mg/24 hours, which is the minimum effective dose.
Following a minimum additional 4 weeks, may increase dosage to maximum dosage of 13.3 mg/24 hours.
Mild-to-Moderate Alzheimer’s Disease and Parkinson’s Disease Dementia: EXELON PATCH 9.5 mg/24 hours or 13.3 mg/24 hours once daily.
( 2.1 ) Severe Alzheimer’s Disease: EXELON PATCH 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 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 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 EXELON PATCH is 9.5 mg/24 hours or 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.
Severe Alzheimer’s Disease The effective dosage of EXELON PATCH in patients with severe Alzheimer’s disease is 13.3 mg/24 hours administered once per day; replace with a new patch every 24 hours.
Interruption of Treatment If dosing is interrupted for 3 days or fewer, restart treatment with the same or lower strength EXELON PATCH.
If dosing is interrupted for more than 3 days, restart treatment with the 4.6 mg/24 hours EXELON PATCH and titrate as described above.
2.2 Dosing in Specific Populations Dosing Modifications in Patients with Hepatic Impairment Consider using the 4.6 mg/24 hours EXELON PATCH as both the initial and maintenance dose in patients with mild (Child-Pugh score 5 to 6) to moderate (Child-Pugh score 7 to 9) hepatic impairment [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 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 less than 6 mg of oral rivastigmine can be switched to the 4.6 mg/24 hours EXELON PATCH.
A patient who is on a total daily dose of 6 mg to 12 mg of oral rivastigmine can be switched to the 9.5 mg/24 hours EXELON PATCH.
Instruct patients or caregivers to apply the first patch on the day following the last oral dose.
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 for 30 seconds until the edges stick well when applying to clean, dry, hairless, intact healthy skin in a place that will not be rubbed against by tight clothing.
Use the upper or lower back as the site of application because the patch is less likely to be removed by the patient.
If sites on the back are not accessible, apply the patch to the upper arm or chest.
Do not apply to a skin area where cream, lotion, or powder has recently been applied.
(c) Do not apply to skin that is red, irritated, or cut.
(d) Replace the EXELON PATCH with a new patch every 24 hours.
Instruct patients to only wear 1 patch at a time (remove the previous day’s patch before applying a new patch) [see Warnings and Precautions (5.1), Overdosage (10)] .
If a patch falls off or if a dose is missed, apply a new patch immediately, and then replace this patch the following day at the usual application time.
(e) Change the site of patch application daily to minimize potential irritation, although a new patch can be applied to the same general anatomic site (e.g., another spot on the upper back) on consecutive days.
Do not apply a new patch to the same location for at least 14 days.
(f) May wear the patch during bathing and in hot weather.
Avoid long exposure to external heat sources (excessive sunlight, saunas, solariums).
(g) Place used patches in the previously saved pouch and discard in the trash, away from pets or children.
(h) Wash hands with soap and water after removing the patch.
In case of contact with eyes or if the eyes become red after handling the patch, rinse immediately with plenty of water, and seek medical advice if symptoms do not resolve.