After switching to 4.6mg/24 h transdermal patches, provided these are well tolerated after a

minimum of four weeks of treatment, the dose of 4.6 mg/24 h should be increased to

9.5mg/24 h, which is the recommended effective dose.

It is recommended to apply the first transdermal patch on the day following the last oral dose.

 

Method of administration
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. It is not recommended to apply the transdermal patch to the thigh or to the abdomen
due to decreased bioavailability of rivastigmine observed when the transdermal patch is applied
to these areas of the body.
The transdermal patch should be replaced by a new one after 24 hours.

 

Important administration instructions (patients and caregivers should be instructed)
• The previous day’s patch must be removed before applying a new one.
• The patch should be replaced by a new one after 24 hours. Only one patch should be worn
at a time (see sections WARNINGS AND PRECAUTIONS and OVERDOSAGE).
• The patch should not be applied to skin that is red, irritated, or cut. Reapplication to the
exact same skin location within 14 days should be avoided to minimize the potential risk of
skin irritation.
• The transdermal patch should be pressed down firmly for at least 30 seconds 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 (e.g., excessive sunlight,
saunas, solarium) for long periods of time.
• The patch should not be cut into pieces.
• Wash your hands with soap and water after applying/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.

 

 

Special populations
Patients with body weight below 50 kg
Caution should be exercised in titrating these patients as they may experience more adverse
reactions. Carefully titrate and monitor these patients for adverse reactions (e.g., excessive
nausea or vomiting) and consider reducing the dose if such adverse reactions develop (see
section WARNINGS AND PRECAUTIONS).

 

Hepatic impairment
Due to increased exposure in mild to moderate hepatic impairment, as observed with the oral
formulation, dosing recommendations to titrate according to individual tolerability should be
closely followed. Patients with clinically significant hepatic impairment may experience more
dose dependent adverse reactions. Patients with severe hepatic impairment have not been
studied. Particular caution should be exercised in titrating these patients (see sections
WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY –
PHARMACOKINETICS).

 

Renal impairment
No dose adjustment is necessary for patients with renal impairment (see CLINICAL
PHARMACOLOGY – Pharmacokinetics).

 

Paediatric patients (below 18 years)
The use of Exelon in paediatric patients has not been studied and is therefore not
recommended.

 

CONTRAINDICATIONS
The use of Exelon is contraindicated in patients with:
• known hypersensitivity to rivastigmine, to other carbamate derivatives or to the
excipients of the formulation (see section DESCRIPTION AND COMPOSITION -
Excipients)
• previous history of application site reactions suggestive of allergic contact dermatitis with
rivastigmine transdermal patch (see section WARNINGS AND PRECAUTIONS –
Application site reactions and skin reactions)

 

WARNINGS AND 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
section 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 one
time. Patients and their caregivers must be instructed on important administration instructions
for Exelon transdermal patch (see section DOSAGE REGIMEN AND ADMINISTRATION).

 

The incidence and severity of adverse events generally increase with increasing doses,
particularly at dose changes. If treatment is interrupted for more than several days, it should
be re-initiated with 4.6mg/24 h.
Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose related, and may
occur when initiating treatment and/or increasing the dose. 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 DRUG 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
transdermal patches.
 

Other adverse reactions from increased cholinergic activity
As with other cholinergic substances, care must be taken when prescribing Exelon transdermal
patches:

• to patients with sick sinus syndrome or conduction defects (sino-atrial block, atrioventricular block) (see ADVERSE DRUG REACTIONS).
• to patients with active gastric or duodenal ulcers or patients predisposed to these
conditions because rivastigmine may cause increased gastric secretions (see ADVERSE
DRUG REACTIONS).
• 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.

 

 

As with other cholinergic substances, rivastigmine may induce or exacerbate or induce
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 13.3mg/24 h transdermal patch which provide higher exposure (AUC) than that
achieved with twice-daily administration of Exelon 6 mg capsules.
Contact with the eyes should be avoided after handling Exelon transdermal patches (see
NON-CLINICAL SAFETY DATA)

 

 

QT prolongation and torsade de pointes
Electrocardiogram QT prolongation may occur in patients treated with certain cholinesterase
inhibitor products including rivastigmine. Rivastigmine may cause bradycardia which
constitutes a risk factor in the occurrence of torsade de pointes, predominantly in patients with
risk factors. Caution is advised in patients at higher risk of developing torsade de pointes; for
example, those with uncompensated heart failure, recent myocardial infarction,
bradyarrhythmias, hypokalaemia or hypomagnesemia, personal or family history of QT
prolongation, or concomitant use with medicinal products known to induce QT prolongation
and/or torsade de pointes. Clinical monitoring may also be required (see INTERACTIONS).

 

Application site reactions and skin reactions
Skin application site reactions may occur with Exelon Patch and are usually mild or moderate
in intensity (see section ADVERSE DRUG REACTIONS – Application site 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 (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 section
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 allergic dermatitis
(disseminated) when administered rivastigmine irrespective of the route of administration
(oral, transdermal). In these cases, treatment should be discontinued (see section
CONTRAINDICATIONS). Patients and caregivers should be instructed accordingly.

 

Special populations
• Patients with body weight below 50 kg may experience more adverse reactions and may
be more likely to discontinue due to adverse reactions. Carefully titrate and monitor these
patients for adverse reactions (e.g., excessive nausea or vomiting) and consider reducing
the dose if such adverse reactions develop (see section DOSAGE REGIMEN AND
ADMINISTRATION).
• Hepatic impairment: Patients with clinically significant hepatic impairment may
experience more adverse reactions. Dosing recommendations to titrate according to
individual tolerability should be closely followed. Patients with severe hepatic impairment
have not been studied. (see sections DOSAGE REGIMEN AND ADMINISTRATION
and CLINICAL PHARMACOLOGY – Pharmacokinetics).

 

Driving and using machines
Alzheimer’s disease may cause gradual impairment of driving performance or compromise
the ability to use machinery. Furthermore, rivastigmine may induce syncope or delirium.
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.

---

ADVERSE DRUG REACTIONS
The overall incidence of adverse events (AEs) in patients treated with Exelon 9.5mg/24 h
transdermal patches was lower than the rate in patients who received 3 to 12 mg/day Exelon
capsule treatment (50.5% with Exelon 9.5mg/24 h transdermal patches vs 63.3% with Exelon
capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse events,
including nausea and vomiting, were the most common adverse events in patients who
received active treatment, and occurred at a substantially lower rate in the Exelon 9.5mg/24 h
transdermal patch group compared to the Exelon capsule group (7.2% vs 23.1% for nausea
and 6.2% vs 17.0% for vomiting; 5.0% and 3.3% of patients on placebo reported nausea and
vomiting, respectively).
Adverse drug reactions from clinical trials in Table 1 and Table 2 are listed by MedDRA
system organ class. Within each system organ class, the adverse drug reactions are ranked by
frequency, with the most frequent reactions first. Within each frequency grouping, adverse
drug reactions are presented in order of decreasing seriousness. In addition, the corresponding
frequency category for each adverse drug reaction is based on the following convention
(CIOMS III): 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).

 

 

*In a 24-week-controlled study in Chinese patients’ somnolence was reported as “common”.
**In a 24-week-controlled study in Japanese patients, application site erythema, application site oedema,
application site pruritus and contact dermatitis were reported as “very common”.

 

 

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, visual hallucination (common).
In patients with dementia associated with 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, erythema, urticaria,
blister, dermatitis allergic.
Very rarely reported: tachycardia, atrioventricular block, atrial fibrillation, pancreatitis, fall,
seizure. Parkinson’s disease (worsening) 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, allergic dermatitis (disseminated), extrapyramidal symptoms in patients with
Alzheimer’s dementia, tremor, nightmares.

 

 

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: confusion.

 

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.

 

 

 

Application site reactions (skin irritation)
In double-blind controlled clinical trials, application site reactions were mostly mild to
moderate in severity. The incidence of application site skin reactions leading to
discontinuation was observed in ≤2.3% of Exelon Patch patients. This number was 4.9% and
8.4% in the Chinese population and Japanese population, respectively.
Cases of skin irritation were captured separately on an investigator-rated skin irritation scale.
In this study, the most commonly observed symptoms (skin irritation rating scale) with
Exelon 9.5mg/24 h transdermal patches were very slight (21.8%), mild (12.5%) or moderate
(6.5%) erythema or very slight (11.9%), mild (7.3%) or moderate (5.0%) pruritus. The most
commonly observed severe symptoms with Exelon 9.5mg/24 h transdermal patches were
pruritus (1.7%) and erythema (1.1%). Most skin reactions were limited to the application site
and resulted in discontinuation in only 2.4% of the patients in the Exelon 9.5mg/24 h
transdermal patch group.
See section WARNINGS AND PRECAUTIONS – Application site reactions and skin
reactions.

---

INTERACTIONS
No specific interaction studies have been conducted with Exelon transdermal patches.

Anticipated interactions resulting in a concomitant use not recommended
Metoclopramide

Considering the possibility of an additive extra-pyramidal effect the concomitant use of
metoclopramide and rivastigmine is not recommended.
Drugs acting on cholinergic system

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with
other cholinomimetic drugs due to possible additive effect. Rivastigmine might also interfere
with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine).
Succinylcholine-type muscle relaxants

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type
muscle relaxants during anaesthesia.

Anticipated interactions to be considered
Medicinal products known to prolong the QT interval

Caution is advised when rivastigmine is used in combination with other medicinal products
known to prolong the QT interval (including but not limited to quinidine, amiodarone,
pimozide, halofantrine, cisapride, citalopram, mizolastin, moxifloxacin, erythromycin).
Clinical monitoring may also be required (see WARNINGS AND PRECAUTIONS).

Observed interactions to be considered
Beta-blockers

Additive effects leading to bradycardia (which may result in syncope) have been reported
with the combined use of various beta-blockers (including atenolol) and rivastigmine. Cardioselective beta-blockers are expected to be associated with the greatest risk, but reports have
also been received in patients using other beta-blockers.
Nicotine

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of
rivastigmine by 23% in patients with Alzheimer’s dementia (n=75 smokers and 549 nonsmokers) following rivastigmine oral capsule doses of up to 12 mg/day.

Interactions with commonly used concomitant drugs
No pharmacokinetic interaction was observed between oral 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 oral rivastigmine.
No untoward effects on cardiac conduction were observed following concomitant
administration of digoxin and oral rivastigmine.
Concomitant administration of rivastigmine with commonly prescribed medications, such as
antacids, antiemetics, antidiabetics, centrally acting antihypertensives, -blockers, calcium
channel blockers, inotropic drugs, antianginals, non-steroidal anti-inflammatory agents,
oestrogens, analgesics, benzodiazepines, and antihistamines, was not associated with an
alteration in the kinetics of rivastigmine or an increased risk of clinically relevant untoward
effects.
According to its metabolism, metabolic drug interactions appear unlikely, although
rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other drugs.

---

PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL
Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if
this occurs in humans. No clinical data on exposed pregnancies are available. No effects on
fertility or embryofoetal development were observed in rats and rabbits, except at doses
related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was
observed. Rivastigmine should not be used during pregnancy unless clearly necessary.
Lactation
It is not known if rivastigmine is transferred into human milk. In animals, rivastigmine and/or
metabolites were transferred in breast milk. Therefore, patients on rivastigmine should not
breast-feed.

Females and males of reproductive potential
There is no information available on the effects of rivastigmine in women of child-bearing
potential.
Infertility
There is no information available on the effects of rivastigmine on human fertility. In male
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive
performance of either the parent generation or the offspring of the parents. 

---

OVERDOSAGE
Symptoms
Most cases of accidental overdose of oral rivastigmine have not been associated with any
clinical signs or symptoms and almost all the patients concerned continued rivastigmine
treatment. Where symptoms have occurred, they have included nausea, vomiting, diarrhoea,
abdominal pain, dizziness, tremor, headache, somnolence, bradycardia, confusional state,
hyperhidrosis, hypertension, hallucinations, and malaise. Overdosage with cholinesterase
inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation,
sweating, bradycardia, hypotension, respiratory depression, and convulsions. Muscle
weakness is a possibility and may result in death if respiratory muscles are involved. Due to
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or
syncope may also occur.
Overdose with Exelon patches resulting from misuse/medication errors (application of
multiple patches at a time) has been reported in the post-marketing setting and rarely in
clinical trials. Fatal outcome has been rarely reported with rivastigmine overdose and the
relationship to rivastigmine was unclear. Symptoms of overdose and outcome vary from
patient to patient and the severity of the outcome is not predictably related to the amount of
the overdose. 

Treatment
As rivastigmine has a plasma half-life of about 3.4 hours and a duration of
acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of
asymptomatic overdose all Exelon transdermal patches should be immediately removed, and
no further patch should be applied for the next 24 hours. 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 0.03 mg/kg intravenous atropine
sulfate is recommended, with subsequent doses based on clinical response. Use of
scopolamine as an antidote is not recommended.

---

CLINICAL PHARMACOLOGY
Pharmacotherapeutic group, ATC
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03
Mechanism of action/ Pharmacodynamics (PD)
Rivastigmine is an acetyl- and butyryl-cholinesterase inhibitor of the carbamate type, thought
to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine
released by functionally intact cholinergic neurons. Thus, rivastigmine may have an
ameliorative effect on cholinergic-mediated cognitive deficits associated with 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 3.0 mg dose decreases
acetylcholinesterase (AChE) activity in cerebro spinal fluid (CSF) by approximately 40%
within the first 1.5 hours after administration. Activity of the enzyme returns to baseline
levels about 9 hours after the maximum inhibitory effect has been achieved. In patients with
Alzheimer’s Disease (AD), inhibition of acetylcholinesterase in CSF by oral rivastigmine was
dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition of BuChE
activity in CSF of 14 AD patients treated by oral rivastigmine was similar to that of AChE.

Pharmacokinetics

Absorption
Absorption of rivastigmine from Exelon transdermal patches is slow. After the first dose,
detectable plasma concentrations are observed after a lag time of 0.5 to 1 hour. Cmax is
reached after 10 to 16 hours. After the peak, plasma concentrations slowly decrease over the
remainder of the 24-hour period of application. With multiple dosing (such as 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 hours. At steady state, trough levels are approximately 50% of peak levels, in
contrast to oral administration, with which concentrations fall off to virtually zero between
doses. Although less pronounced than with the oral formulation, exposure to rivastigmine
(Cmax and AUC) increased over-proportionally by a factor of 2.6 when escalating from
4.6mg/24 h to 9.5mg/24 h. The fluctuation index (FI), a measure of the relative difference
between peak and trough concentrations ((Cmax to Cmin)/Cavg), was 0.58 for Exelon 4.6/24 h
transdermal patches and 0.77 for Exelon 9.5mg/24 h transdermal patches, thus demonstrating
a much smaller fluctuation between trough and peak concentrations than for the oral
formulation (FI = 3.96 (6mg/day) and 4.15 (12mg/day)).
The dose of rivastigmine released from the transdermal patch over 24 hours (mg/24h) cannot
be directly equated to the amount (mg) of rivastigmine contained in a capsule with respect to
plasma concentration produced over 24 hours.

The single dose study inter-subject in rivastigmine pharmacokinetic parameters (normalised
to dose/kg bodyweight) was 43% (Cmax) and 49% (AUC0-24h) after transdermal administration
versus 74% and 103%, respectively, after the oral form. The inter-subject variability in a
steady-state study in Alzheimer’s dementia was most 45% (Cmax) and 43% (AUC0-24h) after
use of the transdermal patch, and 71% and 73%, respectively, after administration of the oral
form.
A relationship between drug exposure at steady state (rivastigmine and metabolite NAP226-
90) and bodyweight 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 bodyweight on
drug exposure suggests special attention to patients with very low body weight during uptitration (see WARNINGS AND PRECAUTIONS).
Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the patch
was applied to the upper back, chest, or upper arm and approximately 20-30% lower when
applied to the abdomen or thigh.
There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in
patients with Alzheimer’s disease, except that plasma levels were higher on the second day of
transdermal patch therapy than on the first.

 

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 to 2.7 l/kg.

Metabolism
Rivastigmine is rapidly and extensively metabolized with an apparent elimination half-life in
plasma of approximately 3.4 hours after removal of the transdermal patch. Elimination was
absorption rate limited (flip-flop kinetics), which explains the longer t½ after patch (3.4 h)
versus oral or i.v. administrations (1.4 to 1.7 h). Metabolism is primarily via cholinesterasemediated hydrolysis to the metabolite NAP226-90. In vitro, this metabolite shows minimal
inhibition of acetylcholinesterase (<10%). Based on in vitro studies, no pharmacokinetic drug
interactions are expected with drugs metabolized by the following cytochrome isoenzymes:
CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6.
Based on evidence from animal studies, the major cytochrome P450 isoenzymes are
minimally involved in rivastigmine metabolism. Total plasma clearance of rivastigmine was
approximately 130 liters/h after a 0.2 mg intravenous dose and decreased to 70 liters/h after a
2.7 mg intravenous dose, which is consistent with the non-linear, over-proportional
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 compared to oral
treatment. Less NAP226-90 is formed following application of the transdermal patch,
presumably because of the lack of pre-systemic (hepatic first pass) metabolism, in contrast to
oral administration.

Elimination
Unchanged rivastigmine is found in trace amounts in the urine; renal excretion of the
metabolites is the major route of elimination after transdermal patch administation. Following
administration of oral 14C-rivastigmine, renal elimination was rapid and essentially complete
(>90 %) within 24 hours. Less than 1% of the administered dose is excreted in the faeces.

Elderly subjects
Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated
with Exelon transdermal patches.

Subjects with hepatic impairment
No study was conducted with the Exelon transdermal 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. Following a single 3-mg oral dose or multiple 6-
mg twice a day oral doses, the mean oral clearance of rivastigmine was approximately 60 to
65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9)
hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). These
pharmacokinetic changes had no effect on either the incidence or severity of adverse effects
(see sections DOSAGE REGIMEN AND ADMINISTRATION and WARNINGS AND
PRECAUTIONS).

Subjects with renal impairment
No study was conducted with the Exelon transdermal patches in subjects with renal
impairment. Based on population analysis creatinine clearance did not show any clear effect
on steady state concentrations of rivastigmine or its metabolite. No dosage adjustment is
necessary in patients with renal impairment (see section DOSAGE REGIMEN AND
ADMINISTRATION)

---

CLINICAL STUDIES
Clinical studies in Alzheimer’s Dementia
The efficacy of Exelon transdermal patches (10, 15 and 20) in patients with mild to
moderately severe dementia of the Alzheimer’s type 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 13.3mg/24h 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 controlled studies
Patients involved in a study had an MMSE (Mini-Mental State Examination) score of 10 to
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 ADCS-CGIC
(Alzheimer’s Disease Cooperative Study-Clinician’s Global Impression of Change: 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 such as shopping, retention
of ability to orient oneself to surroundings as well as involvement in activities related to
finances). The 24-week results for the three assessment tools are summarised in Table 4.

Table 4 24-week results for the three assessment tools in patients with mild to
moderate Alzheimer’s dementia

* p≤0.05 versus placebo
ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward
1 Based on ANCOVA with treatment and country as factors and baseline value as a covariate. Negative ADAS-Cog
changes indicate improvement. Positive ADCS-ADL changes indicate improvement.
2 Based on CMH test (van Elteren test) blocking for country. ADCS-CGIC scores <4 indicate improvement.
The results for clinically relevant responders from the 24-week study are provided in Table 5.
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.

Table 5 Results for clinically relevant responders from the 24-week placebocontrolled study in patients with mild to moderate Alzheimer’s
dementia

*p<0.05, **p<0.01 versus placebo
As suggested by compartmental modeling, 9.5mg/24 h transdermal patches exhibited
exposure similar to that provided by an oral dose of 12 mg/day. Similar results were observed
in separately conducted controlled studies in Chinese and Japanese patients with mild to
moderately severe Alzheimer’s dementia.

48-week active comparator-controlled study
Patients involved in the active comparator-controlled study had an initial baseline MMSE
(Mini-Mental State Examination) score of 10 to 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 to 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 two assessment
tools are summarized in Table 6.

Table 6 Mean change from double-blind baseline in ADAS-Cog and ADCSIADL scores over time in patients with mild to moderate Alzheimer’s
dementia

ANCOVA - analysis of covariance, CI – confidence interval, DB – double blind
DLSM – difference in least square means, LOCF – Last Observation Carried Forward.
ADAS-cog scores: A negative difference in DLSM indicates greater improvement in Exelon 15 cm2 as compared
to Exelon 10 cm2
ADCS-IADL scores: A positive difference in DLSM indicates greater improvement in Exelon 15 cm2 as compared
to Exelon 10 cm2
n is the number of patients with an assessment at baseline and the corresponding visit.
The DLSM, 95% CI, and p-value are based on an ANCOVA model adjusted for country and baseline
* p < 0.05

 

Severe Alzheimer’s dementia

24-week controlled study
Patients involved in the controlled study had at baseline an MMSE (Mini-Mental State
Examination) 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 SIB, the ADCS-ADL-SIV and the ADCS-CGIC.
The SIB: the Severe Impairment Battery is a 40-item scale with a range of possible scores
from 0 to 100, with higher scores reflecting higher levels of cognitive function.
The ADCS-ADL-SIV: the Alzheimer’s Disease Cooperative Study Activity of Daily LivingSevere Impairment Version 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: the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of
Change is a comprehensive global assessment of the patient by the physician incorporating
caregiver input. 

The 24-week results for the three assessment tools are summarized in Table 7.
Table 7 24-week results for the three assessment tools in patients with severe
Alzheimer’s dementia

* p≤0.05
MFAS: Modified Full Analysis Set.
LOCF: Last Observation Carried Forward.
LS: Least Squares.
ADCS-CGIC: refers to the number (percent) of patients with no change or improvement in total score.
[1] Obtained from an ANCOVA model with treatment and pooled center as factors, and baseline score (SIB or ADCS-ADLSIV, respectively) as a covariate.
[2] 95% confidence interval (CI) based on the normal approximation.
[3] From Cochran-Mantel-Haenszel (CMH) chi-square test, adjusting for pooled center.

 

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 (Mini-Mental State Examination) score at screening of 10 to 24. Efficacy has been
established by the use of two 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 to 26. Efficacy was evaluated by the use of two independent
scales which were assessed at regular intervals. These include the MDRS (Mattis Dementia
Rating Scale, a performance-based measure of cognition) and the ADCS-ADL.
The 24-week results for the two scales are summarized in Table 8.

Table 8 24-week results for MDRS and ADCS-ADL scales

NON-CLINICAL SAFETY DATA
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.
Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a
chromosomal aberration test in human peripheral lymphocytes at a dose exceeding 104 times
the foreseen clinical exposure. The in vivo micronucleus test was negative. In addition, the
major metabolite NAP226-90 did not induce structural chromosome aberrations in an in vitro
test indicating that the compound has no genotoxic potential.
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 transdermal patches.
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in
pregnant rats and rabbits gave no indication of teratogenic potential on the part of
rivastigmine. Specific dermal studies in pregnant animals have not been conducted.

Rivastigmine transdermal patches were not phototoxic and considered to be a non-sensitizer.
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 transdermal
patches to induce mild erythema in patients. When administered to rabbit eyes in primary eye
irritation studies, rivastigmine caused reddening and swelling of the conjunctiva, corneal
opacities and miosis which persisted for 7 days. Therefore, the patient/caregiver should avoid
contact with the eyes after handling of the patch (see WARNINGS AND PRECAUTIONS).

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INCOMPATIBILITIES
To prevent interference with the adhesive properties of the transdermal patch, no cream,
lotion, or powder should be applied to the skin area where the Exelon transdermal patch is to
be applied.

STORAGE
See folding box
Exelon Patch should not be used after the date marked “EXP” on the pack
Exelon Patch must be kept out of the reach and sight of children.

INSTRUCTIONS FOR USE AND HANDLING
IMPORTANT: Only one patch should be worn at a time. You must remove the previous
day’s Exelon Patch before applying a new one. Do not cut the patch into pieces.

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Where to apply Exelon Patch
Apply the patch to the upper or lower back, upper arm or chest. Avoid places where the
patch can be rubbed off by tight clothing.
• Before you apply Exelon Patch, make sure that your skin is:
- clean, dry and hairless
- free of any powder, oil, moisturiser, or lotion (that could keep the patch from
sticking to your skin properly)
- free of cuts, rashes and/or irritations.
• Every 24 hours, please gently remove any existing Exelon patch before putting
on a new one. Having multiple patches on your body could expose you 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
(shown in the figures below):
• upper arm, left or right side, or
• chest, left or right side, or
• upper back, left or right side, or
• lower back, left or right side
• Avoid places where the patch can be rubbed off by tight clothing.

When changing your patch, you must remove the previous day’s patch before you apply your
new patch to a different area of skin (for example on the right side of your body one day, then
on the left side the next day). Do not apply a new patch to that same area for at least one
week.

How to apply Exelon Patch

The patch is a thin, opaque, plastic patch that sticks to the skin. Each patch is sealed in a
sachet that protects it until you are ready to put it on. Do not open the sachet or remove a
patch until just before you apply it.

Every 24 hours, please gently remove any existing Exelon patch before putting on a new
one. Having multiple patches on your body could expose you to an excessive amount of
this medicine which could be potentially dangerous.
• Each patch is sealed in its own protective sachet.
You should only open the sachet when you are ready
to apply the patch.
Tear or cut the sachet or 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
second side of the protective liner.
• Then press the patch firmly in place for at least 30
seconds using the palm of the hand to make sure that
the edges stick well.

 

If it helps you, you may write (e.g. 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. You
may wish to experiment with different locations when applying a new patch, to find ones that
are most comfortable for you and where clothing will not rub on the patch.

How to remove 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 on your 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.

How to dispose Exelon Patch
After the patch has been removed, fold it in half 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 your 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.

Can you wear the patch when bathing, swimming, or in the sun?
• Bathing, swimming, or showering should not affect the patch. When swimming, you
can wear the patch under your 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