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ERASTIG 4.6 MG/24 H TRANSDERMAL PATCH

Active substance(s): RIVASTIGMINE / RIVASTIGMINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Erastig 4.6 mg/24 h transdermal patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch releases 4.6 mg rivastigmine per 24 hours.
Each transdermal patch of 5 cm2 contains 9 mg rivastigmine.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal patch.
The drug product is a three-layer matrix transdermal round shaped patch
consisting of backing film, drug (acrylic) matrix containing drug substance,
adhesive (silicone) matrix and furthermore a rectangular release liner.
The outside of the backing layer is translucent, white and black-printed as
follows;
“Rivastigmine, 4.6 mg/24 h”

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.
Erastig is indicated in adults.

4.2

Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in the
diagnosis and treatment of Alzheimer’s dementia. Diagnosis should be made
according to current guidelines. Similar to any treatment initiated in patients with
dementia, therapy with rivastigmine should only be started if a caregiver is available
to regularly administer and monitor the treatment.
Posology

Transdermal patches

Rivastigmine dose load

Rivastigmine in vivo
release rates per 24 h

Erastig 4.6 mg/24 h

9 mg

4.6 mg

Erastig 9.5 mg/24 h

18 mg

9.5 mg

Initial dose
Treatment is started with 4.6 mg/24 h.
After a minimum of four weeks of treatment and if well tolerated according to the
treating physician, this dose should be increased to 9.5 mg/24 h, which is the
recommended effective dose.
Maintenance dose
9.5 mg/24 h is the recommended daily maintenance dose which can be continued for
as long as the patient is deriving therapeutic benefit. Treatment should be temporarily
interrupted if gastrointestinal adverse reactions are observed until these adverse
reactions resolve. Transdermal patch treatment can be resumed at the same dose if
treatment is not interrupted for more than several days. Otherwise treatment should be
re-initiated with 4.6 mg/24 h.
Switching from capsules or oral solution to transdermal patches
Based on comparable exposure between oral and transdermal rivastigmine (see
section 5.2), patients treated with capsules or oral solutions containing rivastigmine
can be switched to Erastig transdermal patches as follows:


A patient on a dose of 3 mg/day oral rivastigmine can be switched to 4.6
mg/24 h transdermal patches.



A patient on a dose of 6 mg/day oral rivastigmine can be switched to 4.6
mg/24 h transdermal patches.



A patient on a stable and well tolerated dose of 9 mg/day oral rivastigmine
can be switched to 9.5 mg/24 h transdermal patches. If the oral dose of 9
mg/day has not been stable and well tolerated, a switch to 4.6 mg/24 h
transdermal patches is recommended.



A patient on a dose of 12 mg/day oral rivastigmine can be switched to 9.5
mg/24 h transdermal patches.

After switching to 4.6 mg/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 9.5 mg/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.
Special populations
Renal impairment: No dose adjustment is necessary for patients with renal
impairment (see section 5.2).
Paediatric population
The safety and efficacy of Erastig in the paediatric population aged 0 to below 18
years have not been established. No data are available.
There is no relevant use of Erastig in the paediatric population aged 0 to below 18
years in the treatment of Alzheimer’s dementia.
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 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
minimise the potential risk of skin irritation.
The transdermal patch should be pressed down firmly until the edges stick well. It can
be used in everyday situations, including bathing and during hot weather.
The transdermal patch should be replaced by a new one after 24 hours. Only one
transdermal patch should be worn at a time (see section 4.9). The transdermal patch
should not be cut into pieces. Patients and caregivers should be instructed
accordingly.

4.3

Contraindications
Hypersensitivity to the active substance, to other carbamate derivatives or to
any of the excipients listed in section 6.1.
Previous history of application site reactions suggestive of allergic contact
dermatitis with rivastigmine patch (see section 4.4).

4.4

Special warnings and precautions for use
The incidence and severity of adverse reactions generally increase with increasing
doses, particularly at dose changes. If treatment is interrupted for more than several
days, it should be re-initiated with 4.6 mg/24 h.
Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related,
and may occur when initiating treatment and/or increasing the dose (see section 4.8).
These adverse reactions occur more commonly in women. Patients who show signs or
symptoms of dehydration resulting from prolonged vomiting or diarrhoea can be
managed with intravenous fluids and dose reduction or discontinuation if recognised
and treated promptly. Dehydration can be associated with serious outcomes.
Patients with Alzheimer’s disease may lose weight whilst taking cholinesterase
inhibitors, including rivastigmine. The patient’s weight should be monitored during
therapy with Erastig transdermal patches.
Care must be taken when prescribing Erastig transdermal patches:


to patients with sick sinus syndrome or conduction defects (sino-atrial block,
atrio-ventricular block) (see section 4.8)



to patients with active gastric or duodenal ulcers or patients predisposed to
these conditions because rivastigmine may cause increased gastric secretions
(see section 4.8)



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

Skin application site reactions may occur with rivastigmine patch and are usually
mild or moderate in intensity. These reactions are not in themselves an indication of
sensitisation. 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, oedema, papules, vesicles) and if symptoms do not significantly
improve within 48 hours after patch removal. In these cases, treatment should be
discontinued (see section 4.3).
Patients who develop application site reactions suggestive of allergic contact
dermatitis to rivastigmine patch and who still require rivastigmine treatment should
only be switched to oral rivastigmine after negative allergy testing and under close
medical supervision. It is possible that some patients sensitised to rivastigmine by
exposure to rivastigmine patch may not be able to take rivastigmine in any form.

There have been rare 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 section 4.3).
Patients and caregivers should be instructed accordingly.
Rivastigmine may exacerbate or induce extrapyramidal symptoms.
Contact with the eyes should be avoided after handling Erastig transdermal patches
(see section 5.3).
Special populations

4.5



Patients with body weight below 50 kg may experience more adverse
reactions and may be more likely to discontinue due to adverse reactions.



Hepatic impairment: Patients with clinically significant hepatic impairment
might experience more adverse reactions (see section 5.2).

Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been conducted with transdermal
rivastigmine patches.
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of
succinylcholine-type muscle relaxants during anaesthesia. Caution is
recommended when selecting anaesthetic agents. Possible dose adjustments or
temporarily stopping treatment can be considered if needed.
In view of its pharmacodynamic effects, rivastigmine should not be given
concomitantly with other cholinomimetic substances and might interfere with
the activity of anticholinergic medicinal products.
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
medicinal products, such as antacids, antiemetics, antidiabetics, centrally
acting antihypertensives, beta blockers, calcium channel blockers, inotropic
agents, 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 interactions with other medicinal
products appear unlikely, although rivastigmine may inhibit the
butyrylcholinesterase mediated metabolism of other substances.

4.6

Fertility, Pregnancy and lactation
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.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine
is excreted into human milk. Therefore, women on rivastigmine should not
breastfeed.

4.7

Effects on ability to drive and use 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. As a consequence, rivastigmine has minor or
moderate influence on the ability to drive and use machines. 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.

4.8

Undesirable effects
The overall incidence of adverse events (AEs) in patients treated with transdermal
patches containing 9.5 mg/24 h rivastigmine was lower than the rate in patients who
received 3 to 12 mg/day rivastigmine capsule treatment (50.5% with transdermal
patches containing 9.5 mg/24 h rivastigmine vs. 63.3% with rivastigmine capsules;
46.0% of patients on placebo reported AEs). Gastrointestinal adverse reactions,
including nausea and vomiting, were the most common adverse reactions in patients
who received active treatment, and occurred at a substantially lower rate in the
rivastigmine 9.5 mg/24 h transdermal patch group compared to the rivastigmine
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 reactions in Table 1 are listed according to MedDRA system organ class and
frequency category. Frequency categories are defined using the following convention:
very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100);
rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated
from the available data).
Table 1 displays the adverse reactions (events reasonably believed to be causally
related to the medicinal product) reported in 291 patients with Alzheimer’s dementia

treated in a specific 24-week double-blind, placebo and active-controlled clinical
study with transdermal rivastigmine patches at a target dose of 9.5 mg/24 h (4.6
mg/24 h titrated to 9.5 mg/24 h).

Table 1
Infections and infestations
Common:

Urinary tract infection

Metabolism and nutrition disorders
Common:

Anorexia

Not known:

Dehydration

Psychiatric disorders
Common:

Anxiety, depression, delirium

Not known:

Hallucinations, aggression, restlessness

Nervous system disorders
Common:

Headache, syncope

Very rare:

Extrapyramidal symptoms

Not known:

Worsening of Parkinson`s disease, seizure

Cardiac disorders
Uncommon:
Not known:

Bradycardia
Atrioventricular block, atrial fibrillation, tachycardia,
sick sinus syndrome

Vascular disorders
Not known:

Hypertension

Gastrointestinal disorders
Common:

Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain

Uncommon:

Gastric ulcer

Not known:

Pancreatitis

Hepatobiliary disorders
Not known:

Hepatitis, elevated liver function tests

Skin and subcutaneous tissue disorders
Common:

Rash

Not known:

Pruritus, erythema, urticaria, vesicles, allergic dermatitis

General disorders and administration site conditions
Common:

Application site skin reactions (e.g. application site
erythema, application site pruritus, application site
oedema, application site dermatitis, application site
irritation), asthenic conditions (e.g. fatigue, asthenia),
pyrexia, weight decreased

Not known:

Fall

When doses higher than 9.5 mg/24 h were used in the above-mentioned study,
dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure
were observed more frequently than with 9.5 mg/24 h or placebo, suggesting a dose
effect relationship. However, these events did not occur at a higher frequency with
Erastig 9.5 mg/24 h transdermal patches than with placebo.
Table 2 shows the most frequent adverse reactions reported during a 76-week period
in an open-label clinical study conducted with rivastigmine transdermal patches in
patients with dementia associated with Parkinson’s disease.

Table 2
Metabolism and nutrition disorders
Common

Dehydration

Psychiatric disorders
Common

Insomnia, anxiety, agitation, visual hallucination,
depression, aggression

Nervous system disorders
Common

Headache, tremor, dizziness, somnolence, bradykinesia,
dyskinesia, hypokinesia, cogwheel rigidity, weight
decrease

Vascular disorders
Common

Hypertension

Gastrointestinal disorders
Common

Abdominal pain

General disorders and administration site conditions
Very common

Fall, application site erythema

Common

Application site irritation, pruritus, rash, fatigue, asthenia,
gait disturbance

In patients with dementia associated with Parkinson’s disease, the following common
adverse reactions have only been observed with rivastigmine capsules and not with
rivastigmine transdermal patches: nausea, vomiting (very common); decreased
appetite, restlesness, headache, worsening of Parkinson’s disease, bradycardia,
diarrhoea, dyspepsia, salivary hypersecretion, sweating increased (common);
dystonia, atrial fibrillation, atrioventricular block (uncommon).
The following adverse reactions have only been observed with capsules and oral
solution containing rivastigmine and not in clinical studies with rivastigmine 9.5
mg/24 h transdermal patches: Dizziness (very common); agitation, somnolence,
malaise, tremor, confusion, sweating increased (common); insomnia, accidental fall,

elevated liver function tests (uncommon); seizures, duodenal ulcers, angina pectoris
(rare); cardiac arrhythmia (e.g. atrioventricular block, atrial fibrillation and
tachycardia), hypertension, pancreatitis, gastrointestinal haemorrhage, hallucination
(very rare); and some cases of severe vomiting were associated with oesophageal
rupture (not known).
Skin irritation
In clinical trials, skin reactions were measured at each visit using a skin irritation
rating scale that rated the degree of erythema, oedema, scaling, fissures, pruritus and
pain/stinging/burning at the application site. The most commonly observed symptom
was erythema which disappeared within 24 hours in the vast majority of patients. In a
24-week double-blind study, the most commonly observed symptoms (skin irritation
rating scale) with rivastigmine 9.5 mg/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 rivastigmine 9.5 mg/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 rivastigmine 9.5 mg/24 h
transdermal patch group.

4.9

Overdose
Symptoms
Most cases of accidental overdose of oral rivastigmine 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 and diarrhoea, hypertension or
hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors
on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg
of oral rivastigmine occurred in one case; following conservative management
the patient fully recovered within 24 hours. Overdose with transdermal
rivastigmine patches resulting from misuse/dosing 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 oral rivastigmine formulations.
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 transdermal rivastigmine patches should
be removed immediately and no further transdermal 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 reactions should be given as necessary.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg
intravenous atropine sulphate is recommended, with subsequent doses based
on clinical response. Use of scopolamine as an antidote is not recommended.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: Psychoanaleptics;
Anticholinesterases, ATC code: N06DA03

Anti-dementia

drugs;

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate
type, thought to facilitate cholinergic neurotransmission by slowing the
degradation of acetylcholine released by functionally intact cholinergic
neurones. Thus, rivastigmine may have an ameliorative effect on cholinergicmediated cognitive deficits in dementia 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 mg dose decreases acetylcholinesterase (AChE) activity in 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,
inhibition of AChE in CSF by oral rivastigmine was dose-dependent up to 6
mg given twice daily, the highest dose tested.
Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer patients
treated by oral rivastigmine was similar to that of AChE.
Clinical studies in Alzheimer’s dementia
The efficacy of transdermal rivastigmine patches in patients with Alzheimer’s
dementia has been demonstrated in a 24-week double-blind core study and its
open-label extension phase. Patients involved in this study had an MMSE
(Mini-Mental State Examination) 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, 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 (Alzheimer’s Disease Cooperative
Study – Activities of Daily Living, 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 24week results for the three assessment tools are summarised in Table 3.

Table 3

ITT-LOCF population
ADAS-Cog

Transdermal
rivastigmine patches
9.5 mg/24 h
N = 251

(n=248)
Mean baseline ± SD
27.0 ± 10.3
Mean change at week 24 ± SD -0.6 ± 6.4
p-value versus placebo
0.005*1
ADCS-CGIC
(n=248)
Mean score ± SD
3.9 ± 1.20
p-value versus placebo
0.010*2
ADCS-ADL
(n=247)
Mean baseline ± SD
50.1 ± 16.3
Mean change at week 24 ± SD -0.1 ± 9.1
p-value versus placebo
0.013*1

Rivastigmine
capsules
12 mg/day
N = 256

Placebo

(n=253)
27.9 ± 9.4
-0.6 ± 6.2
0.003*1

(n=281)
28.6 ± 9.9
1.0 ± 6.8

(n=253)
3.9 ± 1.25
0.009*2

(n=278)
4.2 ± 1.26

(n=254)
49.3 ± 15.8
-0.5 ± 9.5
0.039*1

(n=281)
49.2 ± 16.0
-2.3 ± 9.4

N = 282

* 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 4.
Clinically relevant improvement was defined a priori as at least 4-point
improvement on the ADASCog, no worsening on the ADCS-CGIC, and no
worsening on the ADCS-ADL.

Table 4
Patients with clinically significant response (%)
Transdermal
Rivastigmine
Placebo
rivastigmine patches
capsules
9.5 mg/24 h
12 mg/day
N = 251
N = 256
N = 282
17.4
19.0
10.5

ITT-LOCF population
At least 4 points
improvement on ADASCog
with no worsening on
ADCS-CGIC and ADCS0.037*
ADL

0.004*

p-value versus placebo
*p<0.05 versus placebo
As suggested by compartmental modelling, 9.5 mg/24 h transdermal patches
exhibited exposure similar to that provided by an oral dose of 12 mg/day.

5.2

Pharmacokinetic properties
Absorption
Absorption of rivastigmine from transdermal patches is slow. After the first
dose, detectable plasma concentrations are observed after a lag time of 0.5-1
hour. Cmax is reached after 10-16 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 transdermal patch
is replaced with a new one, plasma concentrations initially decrease slowly for
about 40 minutes on average, until absorption from the newly applied
transdermal patch becomes faster than 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 4.6 mg/24 h to 9.5 mg/24 h. The fluctuation index (FI), a
measure of the relative difference between peak and trough concentrations
((Cmax-Cmin)/Cavg), was 0.58 for transdermal patches containing 4.6 mg/24 h
rivastigmine and 0.77 for transdermal patches containing 9.5 mg/24 h
rivastigmine, thus demonstrating a much smaller fluctuation between trough
and peak concentrations than for the oral formulation (FI = 3.96 (6 mg/day)
and 4.15 (12 mg/day)).
The dose of rivastigmine released from the transdermal patch over 24 hours
(mg/24 h) 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 inter-subject variability 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-patient variability in a steady-state
study in Alzheimer’s dementia was at 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 active substance 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 active substance exposure suggests special attention to patients
with very low body weight during up-titration (see section 4.4).
Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest
when the transdermal 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 1.8-2.7 l/kg.
Biotransformation
Rivastigmine is rapidly and extensively metabolised 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 transdermal patch (3.4 h) versus oral or
intravenous administrations (1.4 to 1.7 h). Metabolism is primarily via
cholinesterase-mediated hydrolysis to the metabolite NAP226-90. In vitro, this
metabolite shows minimal inhibition of acetylcholinesterase (<10%). Based on
evidence from in vitro and animal studies, the major cytochrome P450
isoenzymes are minimally involved in rivastigmine metabolism. Total plasma
clearance of rivastigmine was approximately 130 l/h after a 0.2 mg
intravenous dose and decreased to 70 l/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 transdermal 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 presystemic (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
administration. 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 transdermal rivastigmine patches.
Subjects with hepatic impairment
No study was conducted with transdermal rivastigmine 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.
Subjects with renal impairment
No study was conducted with transdermal rivastigmine 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.

5.3

Preclinical 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.
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. 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
transdermal rivastigmine 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 section 4.4)

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Film:
Drug matrix:
Adhesive matrix:
Printing ink:

Polyester film
Fluoro-coated polyester film
Acrylic adhesive , Acrylates copolymer poly(butyl
methacrylat-co-methyl methacrylat)
Silicone adhesive
Black printing ink

6.2

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
medicinal product is to be applied.

6.3

Shelf life
2 years

6.4

Special precautions for storage
Store in the original package in order to protect from light.
Keep the transdermal patch in the sachet until use.
This medicinal product does not require any special temperature storage
conditions

6.5

Nature and contents of container
Primary packaging material

Erastig 4.6 mg/24 h transdermal patches are individually packed in child-resistant
heat-sealed sachets made of a paper/polyethylene terephthalate
(PET)/aluminium/polyacrylonitrile (PAN) multi-laminated material.
One sachet contains one transdermal patch.
Secondary packaging material
The sachets are packed in a carton.
Available in packs containing 7, 10, 30, 60 and 90 sachets and in multipacks
containing 60 (2 x 30) and 90 (3 x 30) sachets.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Used transdermal patches should be folded in half, with the adhesive side
inwards, placed in the original sachet and discarded safely and out of the reach
and sight of children. Any used or unused transdermal patches should be
disposed of in accordance with local requirements or returned to the
pharmacy.

7

MARKETING AUTHORISATION HOLDER
Teva UK Limited
Brampton Road
Hampden Park
Eastbourne,
BN22 9AG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/1814

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/02/2013

10

DATE OF REVISION OF THE TEXT
18/10/2013

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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