Exelon Patch

Exelon Patch

rivastigmine

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Rivastigmine.
Description
Each patch of 5 cm2 contains rivastigmine base 9 mg, in vivo release rate of 4.6 mg/24 hrs.
Each patch of 10 cm2 contains rivastigmine base 18 mg, in vivo release rate of 9.5 mg/24 hrs.
Each patch of 15 cm2 contains rivastigmine base 27 mg, in vivo release rate of 13.3 mg/24 hrs.
Each patch is a thin, matrix-type transdermal patch consisting of 3 layers. The outside of the backing layer is beige and labelled for each patch dose as follows: "Exelon Patch 5" and "AMCX", "Exelon Patch 10" and "BHDI", or "Exelon Patch 15" and "CNFU".
It also contains the following excipients: Vitamin E, poly butylmethacrylate, methyl-methacrylate, acrylic copolymer, silicone oil.
Action
Brain-selective cholinesterase inhibitor.
Pharmacology: Pharmacodynamics: Mechanism of Action: Pathological changes in dementia eg, Alzheimer's disease involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are known to be involved in attention, learning and memory and other cognitive processes. Rivastigmine, a brain-selective acetyl- and butyryl-cholinesterase inhibitor of the carbamate type, is thought to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by functionally intact cholinergic neurons. Data from animal studies indicate that rivastigmine selectively increases the availability of acetylcholine in the cortex and hippocampus. Thus, Exelon may have an ameliorative effect on cholinergic-mediated cognitive deficits associated with Alzheimer's disease (AD) and with Parkinson's disease. In addition, there is some evidence that cholinesterase inhibition could slow the formation of amyloidogenic β-amyloid-precursor protein (APP) fragments and thus, of amyloid plaques, which are one of the main pathological features of Alzheimer's disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that temporarily inactivates the enzymes. In healthy young men, an oral 3-mg dose decreases acetylcholinesterase (AChE) activity in cerebrospinal fluid (CSF) by approximately 40% within the first 1.5 hrs after administration. Activity of the enzyme returns to baseline levels about 9 hrs after the maximum inhibitory effect has been achieved. Butyrylcholinesterase (BuChE) activity in CSF was transiently inhibited and was no longer different from baseline after 3.6 hrs in healthy young volunteers. In patients with Alzheimer's disease, inhibition of acetylcholinesterase in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of BuChE activity in CSF of AD patients by rivastigmine was similar to that of AchE, with a change from baseline of >60% after 6 mg given twice daily. The effect of rivastigmine on AChE and BuChE activity in CSF was sustained after 12 months administration, the longest time studied. Statistically significant correlations were found between the degree of inhibition by rivastigmine of AChE and BuChE in the CSF and changes on a compound measure of cognitive performance in AD patients; however, only BuChE inhibition in CSF was significantly and consistently correlated with improvements in speed-, attention- and memory-related subtests.
Clinical Studies: Clinical Studies in Alzheimer's Dementia: The efficacy of Exelon patches (10, 15 and 20) in patients with mild to moderately severe dementia of the Alzheimer's dementia has been demonstrated in a 24-week double-blind, placebo-controlled core study and its open-label extension phase and in a 48 week double-blind active comparator study.
The efficacy of Exelon patch 15 in patients with severe dementia of the Alzheimer's type has been demonstrated in a 24-week double-blind study.
Mild to Moderate Alzheimer's Dementia: 24-Week Placebo-Controlled Study: Patients involved in the placebo-controlled study had an mini-mental state examination (MMSE) score of 10-20. Efficacy was established by the use of independent, domain-specific assessment tools which were applied at regular intervals during the 24-week treatment period. These include the ADAS-Cog (a performance-based measure of cognition) and the Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC: A comprehensive global assessment of the patient by the physician incorporating caregiver input) and the ADCS-ADL (a caregiver-rated assessment of the activities of daily living including personal hygiene, feeding, dressing, household chores eg, shopping, retention of ability to orient oneself to surroundings as well as involvement in activities related to finances). The 24-week results for the 3 assessment tools are summarized in Table 1. (See Table 1.)

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The results for clinically relevant responders from the 24-week study are provided in Table 2. Clinically relevant improvement was defined a priori as at least 4-point improvement on the ADAS-cog, no worsening on the ADCS-CGIC and no worsening on the ADCS-ADL. (See Table 2.)

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48-Week Active Comparator Controlled Study: Patients involved in the active comparator controlled study had an initial baseline MMSE score of 10-24. The study was designed to compare the efficacy of the Exelon Patch 15 versus the Exelon Patch 10 during a 48-week double blind treatment phase in Alzheimer's disease patients who demonstrated functional and cognitive decline after an initial 24-48 week open-label treatment phase while on a maintenance dose of Exelon Patch 10. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of ≥2 points from the previous visit or a decrease of ≥3 points from baseline. Efficacy was established by the use of independent, domain-specific assessment tools which were applied at regular intervals during the 48-week treatment period. These include the ADAS-Cog (a performance-based measure of cognition) and the ADCS-instrumental ADL (a subscale from the ADCS-ADL activities of daily living scale assessing instrumental activities which are thought to involve more complex cognitive activities and represent clinically meaningful functional activities of daily living, which include maintaining finances, meal preparation, shopping, ability to orient oneself to surroundings, able to be left unattended, etc). The 48-week results for the 2 assessment tools are summarized in Table 3. (See Table 3.)

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Severe Alzheimer's Dementia: 24-Week Controlled Study: Patients involved in the controlled study had at baseline an MMSE score of ≥3 and ≤12. The study was designed to compare the efficacy of Exelon Patch 15 versus Exelon Patch 5 during a 24-week double blind treatment phase in severe Alzheimer's disease. Efficacy was established by the use of independent, domain-specific assessment tools. These include the severe impairment battery (SIB), the Alzheimer's disease cooperative study activity of daily living-severe impairment version (ADCS-ADL-SIV) and the Alzheimer's disease cooperative study-clinical global impression of change (ADCS-CGIC).
The SIB is a 40-item scale with a range of possible scores from 0-100, with higher scores reflecting higher levels of cognitive function.
The ADCS-ADL-SIV is a caregiver-based scale consisting of 19 items designed to assess the patient's performance of both basic and instrumental activities of daily living, which had been used in several studies in moderate to severe Alzheimer's dementia. The total score ranges from 0-54, with higher scores indicating better function.
The ADCS-CGIC is a comprehensive global assessment of the patient by the physician incorporating caregiver input.
The 24-week results for the 3 assessment tools are summarized in Table 4. (See Table 4.)

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Clinical Studies in Dementia Associated with Parkinson's Disease: The efficacy of Exelon capsules in patients with dementia associated with Parkinson's disease was demonstrated in a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study were to have an MMSE score at screening of 10-24. Efficacy has been established by the use of 2 independent scales which were assessed at regular intervals during a 6-month treatment period: The ADAS-Cog, a measure of cognition and the global measure ADCS-CGIC.
The efficacy of Exelon transdermal patch in dementia associated with Parkinson's disease was investigated in an open-label safety study. Patients involved in this study were to have an MMSE score at screening of 10-26. Efficacy was evaluated by the use of 2 independent scales which were assessed at regular intervals. These include the mattis dementia rating scale (MDRS), a performance-based measure of cognition and the ADCS-ADL.
The 24-week results for the 2 scales are summarised in Table 5. (See Table 5.)

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Pharmacokinetics: Absorption: Absorption of rivastigmine from Exelon patches is slow. After the 1st dose, detectable plasma concentrations are observed after a lag time of 0.5-1 hr. Concentrations then rise slowly and typically after 8 hrs reach levels close to maximum, although maximum values peak plasma concentration (Cmax) are often reached at later times (10-16 hrs). After the peak, plasma concentrations slowly decrease over the remainder of the 24-hr period of application. With multiple dosing (eg, at steady state), after the previous patch is replaced with a new one, plasma concentrations initially decrease slowly for about 40 min on average, until absorption from the newly applied patch becomes faster than the elimination and plasma levels begin to rise again to reach a new peak at approximately 8 hrs. At steady state, trough levels are approximately 50% of peak levels, in contrast to oral dosing, with which concentrations fall off to virtually zero between doses (see Figures 1 and 2). This time course of plasma concentrations is observed with all patch strengths (sizes) in the investigated range of Exelon Patch 5 to Exelon Patch 20. Although less pronounced than with the oral formulation, exposure to rivastigmine [Cmax and area under the concentration-time curve (AUC)] increased over-proportionally with rising patch doses. Escalating from Exelon Patch 5 to Exelon Patch 20, the increase in rivastigmine AUC relative to the lowest dose of Exelon Patch 5 was 2.6-, 4.9- and 7.8-fold for Exelon Patch 10, Exelon Patch 15 and Exelon Patch 20, respectively. The fluctuation index (FI) ie, a measure of the relative difference between peak and trough concentrations [(Cmax-Cmin)/Cavg], was in the range 0.57-0.77 for the patch thus, demonstrating a much smaller fluctuation between trough and peak concentrations than for the oral formulation (FI=3.96-6.24). As determined by compartmental modeling the Exelon Patch 20 exhibited exposure (AUC24hrs) in a typical patient equivalent to that which would be provided by an oral dose of about 9-10 mg twice daily (ie, 18-20 mg/day), while Exelon Patch 10 exhibited exposure equivalent to that provided by an oral dose of about 6 mg twice daily (ie, 12 mg/day). (See Figures 1 and 2.)

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In a single-dose study directly comparing the patch versus oral administration, the inter-subject variability in rivastigmine pharmacokinetic parameters (normalized to dose/kg body weight) was 43% (Cmax) and 49% (AUC0-24 hrs) after the patch versus 74% and 103%, respectively, after the oral capsule. Similarly, inter-subject variability in rivastigmine pharmacokinetic parameters was lower after the patch than after the oral capsule in a steady-state study in Alzheimer's dementia patients given repeated doses. The inter-patient variability was at most 45% (Cmax) and 43% (AUC0-24 hrs) after the patch, while 71% and 73%, respectively, after the oral form.
A relationship between drug exposure at steady-state (rivastigmine and metabolite NAP226-90) and body weight was observed in Alzheimer's dementia patients. 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. The effect of body weight on drug exposure suggests special attention to patients with very low body weight during up-titration (see Dosage & Administration).
Rivastigmine was well released from the transdermal system over a 24-hr dermal application with approximately 50% of the drug load 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 3 other sites is available, but the practitioner should keep in mind 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, except that with patch treatment plasma levels on the 2nd day were higher than on the first.
The pharmacokinetic profile of rivastigmine transdermal patches was comparable in patients with Alzheimer's disease and in patients with dementia associated with Parkinson's disease.
Distribution: Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brain barrier and has an apparent volume of distribution in the range of 1.8-2.7 L/kg.
Metabolism: Rivastigmine is rapidly and extensively metabolized with an apparent elimination half-life (t½) in plasma of approximately 3.4 hrs after patch removal. Elimination was absorption rate limited (flip-flop kinetics), which explains the longer t½ after patch (3.4 hrs) versus oral or IV administrations (1.4-1.7 hrs). Metabolism is primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. 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. Total plasma clearance of rivastigmine was approximately 130 L/hr after a 0.2 mg IV dose and decreased to 70 L/hr after a 2.7 mg IV dose, which is consistent with the non-linear, overproportional pharmacokinetics of rivastigmine due to saturation of its elimination.
The metabolite-to-parent AUC ratio was around 0.7 after patch 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.
Elimination: Unchanged rivastigmine is found in trace amounts in the urine; renal excretion of the metabolites is the major route of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hrs. Less than 1% of the administered dose is excreted in the faeces.
Elderly: Age had no impact on the exposure to rivastigmine in Alzheimer's disease patients treated with Exelon patches.
Hepatic Impairment: No study was conducted with the Exelon patches in subjects with hepatic impairment. After oral administration, the Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Renal Impairment: No study was conducted with the Exelon patches in subjects with renal impairment. After oral administration, Cmax and AUC of rivastigmine were more than twice as high in Alzheimer patients with moderate renal impairment compared with healthy subjects; however, there were no changes in Cmax and AUC of rivastigmine in Alzheimer patients with severe renal impairment.
Toxicology: Nonclinical Safety Data: Acute Toxicity: The estimated oral LD50 values in mice were 5.6 mg base/kg (males) and 13.8 mg base/kg (females). The estimated oral LD50 values in rats were 8.1 mg base/kg (males) and 13.8 mg base/kg (females).
Repeated-Dose Toxicity: Oral and topical repeated-dose toxicity studies in mice, rats, rabbits, dogs and minipigs revealed only effects associated with an exaggerated pharmacological action. No target organ toxicity was observed. Oral and topical dosing in animal studies was limited due to the sensitivity of the animal models used.
Mutagenicity: Rivastigmine was not mutagenic in vitro tests for gene mutation and primary DNA damage. In tests for chromosomal damage in vitro, a small increase in the number of cells carrying chromosomal aberrations occurred at very high concentrations. However, as there was no evidence of clastogenic activity in the more relevant in vivo micronucleus test assessing chromosomal damage test, it is most likely that the in vitro findings were false-positive observations.
Carcinogenicity: No evidence of carcinogenicity was found in oral and topical studies in mice and in an oral study in rats at the maximum tolerated dose. The exposure to rivastigmine and its metabolites was approximately equivalent to human exposure with highest doses of rivastigmine capsules and patches.
Reproductive Toxicity: Oral studies in pregnant rats and rabbits with dose levels up to 2.3 mg base/kg/day gave no indication of teratogenic potential on the part of rivastigmine. Similarly, there was no evidence of adverse effects of rivastigmine on fertility, reproductive performance or in utero or postnatal growth and development in rats at given dose levels up to 1.1 mg base/kg/day. Specific dermal studies in pregnant animals have not been conducted.
Dermal Toxicity: Rivastigmine patches were not phototoxic. In some other dermal toxicity studies, a mild irritant effect on the skin of laboratory animals, including controls, was observed. This may indicate a potential for Exelon patches to induce mild erythema in patients.
Indications/Uses
Treatment of patients with mild to moderately severe dementia of the Alzheimer type and associated with Parkinson's disease; severe dementia of the Alzheimer's type.
Dosage/Direction for Use
Dosage: See Table 6. (See Table 6.)

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Mild to Moderate Severe Dementia of Alzheimer's Type and Associated with Parkinson's Disease: Initial and Titration Dose to the Effective Dose: Treatment is started with Exelon Patch 5 once a day.
After a minimum of 4 weeks of treatment and if well-tolerated, this dose should be increased to Exelon Patch 10, the recommended effective dose which can be continued for as long as therapeutic benefit for the patient exists.
Individual responses to rivastigmine may vary and some patients may derive additional benefit from higher doses. Subsequent increases to Exelon Patch 15 and then to Exelon Patch 20 should always be based on good tolerability of the current dose and may be considered only after a minimum of 4 weeks of treatment at each dose level.
Severe Dementia of the Alzheimer's Type: Initial and Titration Dose to the Effective Dose: Treatment is started with Exelon Patch 5 once a day. Subsequently the dose should be increased to Exelon Patch 10 and then to Exelon Patch 15 which is the demonstrated effective dose. These dose increases should always be based on good tolerability of the current dose and may be considered only after a minimum of 4 weeks of treatment at each dose level.
Interruption of Treatment: Treatment should be temporarily interrupted if gastrointestinal adverse effects and/or worsening of existing extrapyramidal symptoms (eg, tremor) are observed until these adverse effects resolve. Patch treatment can be resumed at the same dose if treatment is not interrupted for >3 days. Otherwise treatment should be re-initiated with Exelon Patch 5.
If adverse effects persist on re-initiation of therapy, the dose should be temporarily reduced to the previous well-tolerated dose.
Switching from Capsules or Oral Solution: Patients treated with Exelon capsules or oral solution may be switched to Exelon patches as follows: A patient who is on a dose of oral rivastigmine <6 mg/day can be switched to Exelon Patch 5; a patient who is on a dose of oral rivastigmine 6-12 mg/day may be directly switched to Exelon Patch 10.
It is recommended to apply the 1st patch on the day following the last oral dose.
Renal Impairment: No dose adjustment is necessary for patients with renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Administration: Exelon transdermal patches should be applied once a day to clean, dry, hairless, intact healthy skin on the upper or lower back, upper arm or chest, in a place which will not be rubbed by tight clothing.
The patch should be replaced by a new one after 24 hrs.
For Patients and Caregivers: The previous day's patch must be removed before applying a new one. The patch should be replaced by a new one after 24 hrs. Only 1 patch should be worn at a time (see Precautions and Overdosage).
The patch should not be applied to skin that is red, irritated or cut. It is recommended to change the application site daily to avoid potential irritation, although consecutive patches can be applied to the same general anatomic site (eg, another spot on the upper back).
The patch should be pressed down firmly for at least 30 sec using the palm of the hand until the edges stick well.
If the patch falls off, a new one should be applied for the rest of the day, then it should be replaced at the same time as usual the next day.
The patch can be used in everyday situations, including bathing and during hot weather. The patch should not be exposed to any external heat sources (eg, excessive sunlight, saunas, solarium) for long periods of time.
The patch should not be cut into pieces.
Overdosage
Symptoms: Most cases of accidental overdosage have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting, diarrhoea, hypertension and hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur.
Ingestion of 46 mg has occurred in 1 case; following conservative management the patient fully recovered within 24 hrs.
Overdosage with Exelon patches resulting from misuse/medication errors (application of multiple patches at a time) has been reported in the post-marketing setting. The typical symptoms reported among these cases are similar to those seen with cases of overdose associated with Exelon oral formulations.
Treatment: As rivastigmine has a plasma t½ of about 3.4 hrs and a duration of acetylcholinesterase inhibition of about 9 hrs, it is recommended that in cases of asymptomatic overdose, all Exelon patches should be immediately removed and no further patch should be applied for the next 24 hrs. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse events should be given as necessary.
In massive overdose, atropine can be used. An initial dose of atropine sulfate IV 0.03 mg/kg is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote is not recommended.
Contraindications
Hypersensitivity to rivastigmine, other carbamate derivatives or to any of the excipients of Exelon Patch. Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine transdermal patch (see Precautions).
Special Precautions
Medication Misuse and Dosing Errors Resulting in Overdose: Medication misuse and dosing errors with Exelon transdermal patch have resulted in serious adverse reactions; some cases have required hospitalization and rarely, led to death (see Overdosage). The majority of medication misuse and dosing errors have involved not removing the old patch when putting on a new one and the use of multiple patches at 1 time. Patients and their caregivers must be instructed on important administration instructions for Exelon transdermal patch (see Dosage & Administration).
Gastrointestinal Disorders: The incidence and severity of adverse events generally increase with increasing doses, particularly at dose changes. If treatment is interrupted for >3 several days, it should be re-initiated with Exelon Patch 5.
Gastrointestinal disorders eg, nausea, vomiting and diarrhoea may occur when initiating treatment and/or increasing the dose. They may respond to a dose reduction. In other cases, use of Exelon patches has been discontinued. Patients who show signs or symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be managed with IV fluids and dose reduction or discontinuation if recognized and treated promptly. Dehydration can be associated with serious outcomes (see Adverse Reactions).
Weight Loss: Patients with Alzheimer's disease may lose weight while taking cholinesterase inhibitors, including rivastigmine. The patient's weight should be monitored during therapy with Exelon patches.
Other Adverse Reactions from Increased Cholinergic Activity: As with other cholinergic substances care must be taken when prescribing Exelon patches: To patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see Adverse Reactions); to patients with active gastric or duodenal ulcers or patients predisposed to these conditions because gastric acid secretions may be increased; to patients predisposed to urinary obstruction and seizures because cholinomimetics may induce or exacerbate these diseases; to patients with a history of asthma or obstructive pulmonary disease.
Like other cholinomimetics, rivastigmine may exacerbate extrapyramidal symptoms. In patients with dementia associated with Parkinson's disease who were treated with Exelon capsules, worsening of parkinsonian symptoms, particularly tremor, has been observed. Such adverse events may also occur with Exelon patches, particularly with Exelon Patch 15 and Exelon Patch 20 which provide higher exposure (AUC) than that achieved with twice-daily administration of Exelon 6 mg capsules.
Application Site Reactions and Skin Reactions: Skin application site reactions may occur with Exelon Patch and are usually mild or moderate in intensity (see Adverse Reactions). 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 (eg, increasing erythema, edema, papules, vesicles) and if symptoms do not significantly improve within 48 hrs after patch removal. In these cases, treatment should be discontinued (see Contraindications).
In patients who develop application site reactions suggestive of allergic contact dermatitis to Exelon Patch 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 post-marketing reports of patients experiencing disseminated skin hypersensitivity reactions when administered rivastigmine irrespective of the route of administration (oral, transdermal). In these cases, treatment should be discontinued (see Contraindications). Patients and caregivers should be instructed accordingly.
Special Populations: Patients with body weight <50 kg may experience more adverse events and may be more likely to discontinue due to adverse events. Carefully titrate and monitor these patients for adverse reactions (eg, excessive nausea or vomiting) and consider reducing the dose if such adverse reactions develop (see Dosage & Administration).
Hepatic Impairment: Patients with clinically significant hepatic impairment might experience more adverse events. Particular caution should be exercised in titrating these patients above the recommended maintenance dose of Exelon Patch 10 (see Pharmacology: Pharmacokinetics under Actions).
Effects on the Ability to Drive or Operate Machinery: Alzheimer's and Parkinson's disease dementia may cause gradual impairment of driving performance or compromise the ability to use machinery. Rivastigmine may induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. Therefore, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.
Use in Pregnancy: In animal studies, rivastigmine was not teratogenic. However, the safety of Exelon in human pregnancy has not been established and it should only be given to pregnant women if the potential benefit outweighs the potential risk for the fetus.
Use in Lactation: It is not known if Exelon is excreted into human milk, and patients on Exelon should therefore, not breastfeed.
Use in Children: In children and adolescents <18 years, rivastigmine is not recommended for use.
Use In Pregnancy & Lactation
Use in Pregnancy: In animal studies, rivastigmine was not teratogenic. However, the safety of Exelon in human pregnancy has not been established and it should only be given to pregnant women if the potential benefit outweighs the potential risk for the fetus.
Use in Lactation: It is not known if Exelon is excreted into human milk, and patients on Exelon should therefore, not breastfeed.
Adverse Reactions
The overall incidence of adverse events in patients treated with Exelon Patch 10 was lower than the rate in patients who received Exelon capsule treatment. Nausea and vomiting were the most common adverse events in patients who received active treatment and occurred at similar rates in both Exelon Patch 20 and capsule groups. However, the rates of both of these events were substantially lower with Exelon Patch 10 group.
The most commonly reported adverse drug reactions are gastrointestinal including nausea and vomiting, especially during titration.
Adverse reactions in Table 7 and Table 8 are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports (see Table 7 and Table 8).

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Additional adverse reactions observed during a 76-week prospective, open-label study in patients with dementia associated with Parkinson's disease treated with Exelon transdermal patches: Dehydration, decreased weight, aggression, hallucination visual (common).
In patients with dementia associated Parkinson's disease the following adverse drug reactions have only been observed in clinical trials with Exelon capsules: Nausea, vomiting (very common); decreased appetite, restlessness, worsening of Parkinson's disease, bradycardia, diarrhoea, dyspepsia, salivary hypersecretion, increased sweating (common); dystonia, atrial fibrillation, atrioventricular block (uncommon).
Adverse Drug Reactions from Post-Marketing Spontaneous Reports: The following additional adverse drug reactions have been identified based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.
Rarely Reported: Hypertension, application site hypersensitivity, pruritus, rash, erythema, urticaria, blister, allergic dermatitis.
Very Rarely Reported: Tachycardia, atrioventricular block, atrial fibrillation, pancreatitis, seizure. Worsening of Parkinson's disease has been observed in patients with Parkinson's disease who were treated with Exelon patches.
Frequency Not Known: Hepatitis, restlessness, sick sinus syndrome, abnormal liver function tests, disseminated cutaneous hypersensitivity reactions.
Additional Adverse Drug Reactions which Have Been Reported with Exelon Capsules or Oral Solution: Very Rare: Severe vomiting associated with oesophageal rupture. Rare: Angina pectoris, myocardial infarction, duodenal ulcers. Common: Tremor, confusion.
Information from Clinical Trials in Patients with Alzheimer's Dementia Treated with Exelon Patches: The following adverse drug reactions were reported in patients with Alzheimer's dementia treated with Exelon patches (see Table 9).

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Information from Clinical Trials in Patients with Severe Alzheimer's Dementia Treated with Exelon Patch 15: The following adverse drug reactions were reported in patients with severe Alzheimer's dementia treated with Exelon patch 15 (see Table 10).

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Application Site Reactions (Skin Irritation): In the 24-week placebo-controlled clinical trial, 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% of placebo patch patients.
In the 48-week active controlled clinical trial, cases of skin irritation were captured as patient or caregiver reported adverse events. The most commonly reported skin irritation events during the first 24 weeks of the double-blind period for Exelon Patch 15 group and Exelon Patch 10 group respectively, were application site erythema (5.7% vs 4.6%) and application site pruritus (3.6% vs 2.8%). The percentages decreased in both Exelon Patch 15 and Exelon Patch 10 treatment groups over time (>24 weeks): Application site erythema (0.8% vs 1.6%) and application site pruritus (0.4% vs 1.2%), respectively. Application site pruritus led to discontinuation in 1.1% of the patients from each of the treatment groups during the total 48 week double-blind treatment phase. Application site reactions were mostly mild or moderate in severity and were rated as severe in <2% of patients.
In the 24-week double-blind, double-dummy, controlled clinical trial in patients with severe Alzheimer's disease, cases of skin irritation were captured as adverse events. The most commonly reported skin irritation events during the 24 weeks for Exelon Patch 15 and Exelon Patch 5 respectively, were application site erythema (13.2% vs 11.7%) and application site pruritus (3.7% vs 2.2%). Application site erythema led to discontinuation in only 0.8% of the patients in 15 cm2 group and in 0.6% of patients in 5 cm2 group. Application site erythema in both groups was mostly mild or moderate in severity.
Skin application site reactions and skin reactions (see Precautions).
A direct comparison of the rate of skin irritation events reported in each of these studies cannot be made due to the difference in data collection methods employed.
Drug Interactions
No specific interaction studies have been conducted with Exelon patches.
Rivastigmine is metabolized mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes thus, no pharmacokinetic interactions are anticipated with other drugs metabolized by these enzymes.
No pharmacokinetic interaction was observed between rivastigmine 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. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.
Concomitant administration of rivastigmine with commonly prescribed medications eg, antacids, antiemetics, antidiabetics, centrally acting antihypertensives, β-blockers, calcium channel blockers, inotropic drugs, antianginals, nonsteroidal anti-inflammatory drugs, estrogens, analgesics, benzodiazepines and antihistamines, was not associated with an alteration in the kinetics of rivastigmine or an increased risk of clinically relevant untoward effects.
In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs and might interfere with the activity of anticholinergic medications.
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anesthesia.
Incompatibilities: To prevent interference with the adhesive properties of the patch, no cream, lotion or powder should be applied to the skin area where the Exelon transdermal patch is to be applied.
Caution For Usage
Instructions for Use and Handling: Only 1 patch should be worn at a time. The previous day's Exelon Patch must be removed before applying a new one. Do not cut the patch into pieces.
Where to Apply Exelon Patch: Before applying the Exelon Patch, make sure that the skin is: Clean, dry and hairless; free of any powder, oil, moisturiser, or lotion (that could keep the patch from sticking to the skin properly); free of cuts, rashes and/or irritations.
Every 24 hrs, gently remove any existing Exelon patch before putting on a new one.
Having multiple patches on the body could expose the patient to an excessive amount of this medicine which could be potentially dangerous.
Apply only one patch per day to only one of the following locations: Left or right side of the upper arm, chest, upper back or lower back.
Avoid places where the patch can be rubbed off by tight clothing.
When changing a patch, apply the new patch to a different area of skin (eg, on the right side of the body one day, then on the left side the next day). Do not apply a new patch to that same area for at least 1 week.
Applying Exelon Patch: The patch is a thin, opaque, plastic patch that sticks to the skin. Each patch is sealed in its own protective sachet. Do not open the sachet or remove a patch until just before applying it.
Every 24 hrs, gently remove any existing Exelon patch before putting on a new one.
Having multiple patches on the body could expose the patient to an excessive amount of medicine which could be potentially dangerous.
Each patch is sealed in its own protective sheet.
Open the sachet only when ready to apply the patch.
Tear or cut the sachet at the notch and remove the patch.
A protective liner covers the adhesive side of the patch. Peel off one side of the protective liner and do not touch the sticky part of the patch with the fingers. Put the sticky side of the patch on the upper or lower back, upper arm or chest and then peel off the 2nd side of the protective liner.
Then press the patch firmly in place for at least 30 sec with the palm of the hand to make sure that the edges stick well. If it helps, write (eg, the day of the week) on the Exelon Patch with a thin ball point pen.
Exelon Patch should be worn continuously until it is time to replace it with a new patch. It is encouraged to try different locations when applying a new patch, to find ones that are most comfortable and where clothing will not rub on the patch.
Removing Exelon Patch: Gently pull at one edge of the Exelon Patch to remove it completely from the skin. In case the adhesive residue is left over the skin, gently soak the area with warm water and mild soap or use baby oil to remove it. Alcohol or other dissolving liquids (nail polish remover or other solvents) should not be used.
Disposing Exelon Patch: After the patch has been removed, fold it in ½ with the adhesive sides on the inside and press them together. Return the used patch to its original sachet and discard safely out of the reach and sight of children. 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.
Bathing, swimming, or showering should not affect the patch. When swimming, one can wear the patch under the swimming costume. Make sure the patch does not loosen during these activities.
The patch should not be exposed to any external heat sources (excessive sunlight, saunas, solarium) for long periods of time.
What to Do if Exelon Patch Falls Off: If the patch falls off, a new patch should be applied for the rest of the day, then replace the patch the next day at the same time as usual.
ATC Classification
N06DA03 - rivastigmine ; Belongs to the class of anticholinesterases. Used in the management of dementia.
Presentation/Packing
Transdermal patch 5 4.6 mg/24 hr x 30's. Transdermal patch 10 9.5 mg/24 hr x 30's. Transdermal patch 15 13.3 mg/24 hr x 30's.
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