Exelon Drug Information
Generic name: RIVASTIGMINE
Cholinesterase Inhibitor [EPC]
Uses of Exelon
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.
Parkinson’s Disease Dementia EXELON PATCH is indicated for the treatment of mild-to-moderate dementia associated with Parkinson’s disease (PDD).
Dosage & Administration of Exelon
Recommended Dosing Initial Dose
Initiate treatment with one 4.6 mg/24 hours EXELON PATCH applied to the skin once daily. 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.
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.
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. 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.
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.
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).
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.
Side Effects of Exelon
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 4516 patients with Alzheimer’s disease during clinical trials worldwide. 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 EXELON PATCH in Study 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 unapproved 17.4 mg/24 hours EXELON PATCH than in those using the 9.5 mg/24 hours EXELON PATCH. The most common adverse reactions in the EXELON PATCH-treated groups that led to treatment discontinuation in this study were nausea and vomiting. 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 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. Table 1: Proportion of Adverse Reactions Observed With a Frequency of Greater Than or Equal to 2% and Occurring at a Rate Greater Than 48-Week International Active Comparator-Controlled Trial (Study 2) Most Common Adverse Reactions In Study 2 of the commonly observed adverse reactions (greater than or equal to 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 3). 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. The adverse reaction severity profile was generally similar for both the EXELON PATCH 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 Severe Alzheimer’s Disease 24-Week US Controlled Trial (Study 3) Most Commonly Observed Adverse Reactions The most common adverse reactions in patients administered EXELON PATCH in the controlled clinical trial, defined as those occurring at a frequency of at least 5% in the 13.3 mg/24 hours EXELON PATCH arm and at a frequency higher than in the 4.6 mg/24 hours EXELON PATCH 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. 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 EXELON PATCH 13.3 mg/24 hours group than in the EXELON PATCH 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 patch group reported mild events than in the 13.3 mg/24 hours patch 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 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. 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 EXELON PATCH patients in a double-blind controlled study and in less than or equal to 3.7% of EXELON PATCH patients in a double-blind controlled study in Japanese patients. Parkinson’s Disease Dementia 76-week International Open-Label Trial (Study 4) EXELON PATCH 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. Treatment with EXELON PATCH was initiated at 4.6 mg/24 hours and if tolerated the dose was increased after 4 weeks to 9.5 mg/24 hours.
EXELON 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 4 Additional adverse reactions observed during the 76-week prospective, open-label study in patients with dementia associated with Parkinson’s disease treated with EXELON PATCH: 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 EXELON 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.
Postmarketing Experience
The following adverse reactions have been identified during post approval use of EXELON Capsules, EXELON Oral Solution, or EXELON PATCH. 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
| Abbreviation: ARs, adverse reactions. *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 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 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 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. | ||||
| Adverse reaction | EXELON PATCH 9.5 mg/24 hours | EXELON PATCH 17.4 mg/24 hours | EXELON Capsule 6 mg twice daily | Placebo |
| Total patients studied | 291 | 303 | 294 | 302 |
| Total percentage of patients with ARs (%) | 51 | 66 | 63 | 46 |
| Nausea | 7 | 21 | 23 | 5 |
| Vomiting* | 6 | 19 | 17 | 3 |
| Diarrhea | 6 | 10 | 5 | 3 |
| Depression | 4 | 4 | 4 | 1 |
| Headache | 3 | 4 | 6 | 2 |
| Anxiety | 3 | 3 | 2 | 1 |
| Anorexia/Decreased appetite | 3 | 9 | 9 | 2 |
| Weight decreased* | 3 | 8 | 5 | 1 |
| Dizziness | 2 | 7 | 7 | 2 |
| Abdominal pain | 2 | 4 | 1 | 1 |
| Urinary tract infection | 2 | 2 | 1 | 1 |
| Asthenia | 2 | 3 | 6 | 1 |
| Fatigue | 2 | 2 | 1 | 1 |
| Insomnia | 1 | 4 | 2 | 2 |
| Abdominal pain upper | 1 | 3 | 2 | 2 |
| Vertigo | 0 | 2 | 1 | 1 |
| Abbreviation: ARs, adverse reactions. | |||
| Adverse reaction | EXELON PATCH 13.3 mg/24 hours | EXELON PATCH 9.5 mg/24 hours | Total |
| Total patients studied | 280 | 283 | 563 |
| Total percentage of patients with ARs leading to discontinuation (%) | 9.6 | 12.7 | 11.2 |
| Vomiting | 1.4 | 0.4 | 0.9 |
| Application-site pruritus | 1.1 | 1.1 | 1.1 |
| Aggression | 0.4 | 1.1 | 0.7 |
| Abbreviations: DB, double blind; ARs, adverse reactions. *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 EXELON PATCH 9.5 mg/24 hours and 18.6% of those treated with EXELON PATCH 13.3 mg/24 hours during the 48-week double-blind treatment period. | ||||||
| Cumulative Week 0 to 48 (DB Phase) | Week 0 to 24 (DB Phase) | Week > 24 to 48 (DB Phase) | ||||
| Adverse reaction | EXELON PATCH 13.3 mg/24 hours | EXELON PATCH 9.5 mg/24 hours | EXELON PATCH 13.3 mg/24 hours | EXELON PATCH 9.5 mg/24 hours | EXELON PATCH 13.3 mg/24 hours | EXELON PATCH 9.5 mg/24 hours |
| Total patients studied | 280 | 283 | 280 | 283 | 241 | 246 |
| Total percentage of patients with ARs (%) | 75 | 68 | 65 | 55 | 42 | 40 |
| Nausea | 12 | 5 | 10 | 4 | 4 | 2 |
| Vomiting | 10 | 5 | 9 | 3 | 3 | 2 |
| Fall | 8 | 6 | 4 | 4 | 4 | 3 |
| Weight decreased* | 7 | 3 | 3 | 1 | 5 | 2 |
| Application-site erythema | 6 | 6 | 6 | 5 | 1 | 2 |
| Decreased appetite | 6 | 3 | 5 | 2 | 2 | < 1 |
| Diarrhea | 6 | 5 | 5 | 4 | 2 | < 1 |
| Urinary tract infection | 5 | 4 | 3 | 3 | 3 | 2 |
| Agitation | 5 | 5 | 4 | 3 | 1 | 2 |
| Depression | 5 | 5 | 3 | 3 | 3 | 2 |
| Dizziness | 4 | 1 | 3 | < 1 | 2 | < 1 |
| Application-site pruritus | 4 | 4 | 4 | 3 | < 1 | 1 |
| Headache | 4 | 4 | 4 | 4 | < 1 | < 1 |
| Insomnia | 4 | 3 | 2 | 1 | 3 | 2 |
| Abdominal pain upper | 4 | 1 | 3 | 1 | 1 | < 1 |
| Anxiety | 4 | 3 | 2 | 2 | 2 | 1 |
| Hypertension | 3 | 3 | 3 | 2 | 1 | 1 |
| Urinary incontinence | 3 | 2 | 2 | 1 | 1 | < 1 |
| Psychomotor hyperactivity | 3 | 3 | 2 | 3 | 2 | 1 |
| Aggression | 2 | 3 | 1 | 3 | 1 | 1 |
| Abbreviation: ARs, adverse reactions. *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 EXELON PATCH 4.6 mg/24 hours and 14.1% of those treated with EXELON PATCH 13.3 mg/24 hours during the 24-week double-blind treatment. | ||
| Adverse reaction | EXELON PATCH 13.3 mg/24 hours | EXELON PATCH 4.6 mg/24 hours |
| Total number of patients studied | 355 | 359 |
| Total percentage of patients with ARs (%) | 75 | 73 |
| Application-site erythema | 13 | 12 |
| Agitation | 12 | 14 |
| Urinary tract infection | 8 | 10 |
| Fall | 8 | 6 |
| Insomnia | 7 | 4 |
| Vomiting | 7 | 3 |
| Diarrhea | 7 | 5 |
| Weight decreased* | 7 | 3 |
| Nausea | 6 | 3 |
| Depression | 5 | 4 |
| Decreased appetite | 5 | 1 |
| Anxiety | 5 | 5 |
| Hallucination | 2 | 5 |
| Adverse reaction | EXELON PATCH |
|---|---|
| Total patients studied | 288 |
| Percentage (%) | |
| Psychiatric disorders | |
| Insomnia | 6 |
| Depression | 6 |
| Anxiety | 5 |
| Agitation | 3 |
| Nervous system disorders | |
| Tremor | 7 |
| Dizziness | 6 |
| Somnolence | 4 |
| Hypokinesia | 4 |
| Bradykinesia | 4 |
| Cogwheel rigidity | 3 |
| Dyskinesia | 3 |
| Gastrointestinal disorders | |
| Abdominal pain | 2 |
| Vascular disorders | |
| Hypertension | 3 |
| General disorders and administration-site conditions | |
| Fall | 12 |
| Application-site erythema | 11 |
| Application-site irritation, pruritus, rash | 3; 5; 2 |
| Fatigue | 4 |
| Asthenia | 2 |
| Gait disturbance | 4 |
Warnings & Cautions for Exelon
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.
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.
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. 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.
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. 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). Patients and caregivers should be instructed accordingly.
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. 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.
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.
Drug Interactions with Exelon
Metoclopramide Due to the risk of additive extra-pyramidal adverse reactions, the concomitant use of metoclopramide and EXELON PATCH is not recommended.
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.
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.
Pregnancy Safety for Exelon
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.
Pediatric Use of Exelon
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.
Contraindications for Exelon
- EXELON PATCH is contraindicated in patients with:
- Known hypersensitivity to rivastigmine, other carbamate derivatives, or other components of the formulation
- Previous history of application-site reactions with rivastigmine transdermal patch suggestive of allergic contact dermatitis. Isolated cases of generalized skin reactions have been described in postmarketing experience.
- History of application-site reactions with rivastigmine transdermal patch suggestive of allergic contact dermatitis.
Overdosage Information for Exelon
Overdose with EXELON PATCH has been reported in the postmarketing setting. 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.
Clinical Studies of Exelon
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 (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 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). 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. 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.
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 (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.
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). 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 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 (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.
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. Patients on a stable dose of memantine were permitted to enter the study. 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. 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.
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)
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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