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ERASTIG 13.3 MG/24 H TRANSDERMAL PATCH

Active substance(s): RIVASTIGMINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Erastig 13.3 mg/24 h Transdermal Patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch releases 13.3 mg of rivastigmine per 24 hours. Each
transdermal patch of 15 cm2 contains 27 mg of rivastigmine.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal patch.
Each transdermal patch is a thin, matrix-type transdermal patch consisting of three
layers. The outside of the backing layer is translucent, white and labelled with
“Rivastigmine, 13.3 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 in vivo release rates
per 24 h

Erastig 4.6 mg/24 h

4.6 mg*

Erastig 9.5 mg/24 h

9.5 mg*

Erastig 13.3 mg/24 h

13.3 mg

* For doses not realisable with this medicinal product other strengths of the medicinal
product are available.
Initial dose
Treatment is started with 4.6 mg/24 h.
Maintenance dose
After a minimum of four weeks of treatment and if well tolerated according to the
treating physician, the dose of 4.6 mg/24 h should be increased to 9.5 mg/24 h, the
daily recommended effective dose, which should be continued for as long as the
patient continues to demonstrate therapeutic benefit.
Dose escalation
9.5 mg/24 h is the recommended daily effective dose which should be continued for
as long as the patient continues to demonstrate therapeutic benefit. If well tolerated
and only after a minimum of six months of treatment at 9.5 mg/24 h, the treating
physician may consider increasing the dose to 13.3 mg/24 h in patients who have
demonstrated a meaningful cognitive deterioration (e.g. decrease in the MMSE)
and/or functional decline (based on physician judgement) while on the recommended
daily effective dose of 9.5 mg/24 h (see section 5.1).
The clinical benefit of rivastigmine should be reassessed on a regular basis.
Discontinuation should also be considered when evidence of a therapeutic effect at
the optimal dose is no longer present.
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 three 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


Paediatric population: There is no relevant use of Erastig in the paediatric
population in the treatment of Alzheimer’s disease.



Patients with body weight below 50 kg: Particular caution should be exercised
in titrating patients with body weight below 50 kg above the recommended
effective dose of 9.5 mg/24 h (see section 4.4). They may experience more
adverse reactions and may be more likely to discontinue due to adverse
reactions.



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 adverse
reactions. Patients with severe hepatic impairment have not been studied.
Particular caution should be exercised in titrating these patients (see sections
4.4 and 5.2).



Renal impairment: No dose adjustment is necessary for patients with renal
impairment (see section 5.2).

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.

Patients and caregivers should be instructed on important administration
instructions:

4.3



The previous day’s patch must be removed before applying a new one every day
(see section 4.9).



The patch should be replaced by a new one after 24 hours. Only one patch should
be worn at a time (see section 4.9).



The 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.

Contraindications
The use of this medicinal product is contraindicated in patients with known
hypersensitivity to the active substance rivastigmine, 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 three
days, it should be re-initiated with 4.6 mg/24 h.
Misuse of the medicinal product and dosing errors resulting in overdose
Misuse of the medicinal product and dosing errors with Erastig Transdermal Patch
have resulted in serious adverse reactions; some cases have required hospitalisation,
and rarely led to death (see section 4.9). Most cases of misuse of the medicinal

product and dosing errors have involved not removing the old patch when putting on
a new one and the use of multiple patches at the same time. Patients and their
caregivers must be instructed on important administration instructions for Erastig
Transdermal Patch (see section 4.2).

Gastrointestinal disorders
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.
Weight loss
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.
Other adverse reactions
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
Skin application site reactions may occur with rivastigmine patch and are usually
mild or moderate in intensity. Patients and caregivers should be instructed
accordingly.
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 allergic
dermatitis (disseminated) when administered rivastigmine irrespective of the route of
administration (oral, transdermal). In these cases, treatment should be discontinued
(see section 4.3).
Other warnings and precautions
Rivastigmine may exacerbate or induce extrapyramidal symptoms.
Contact with the eyes should be avoided after handling Erastig Transdermal Patches
(see section 5.3). Hands should be washed 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.
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 (see
section 4.2). Carefully titrate and monitor these patients for adverse reactions
(e.g. excessive nausea or vomiting) and consider reducing the maintenance
dose to the 4.6 mg/24 h transdermal patch if such adverse reactions develop.



Hepatic impairment: Patients with clinically significant hepatic impairment
may experience more adverse reactions. Dosing recommendations to titrate
according to individual tolerability must be closely followed. Patients with
severe hepatic impairment have not been studied. Particular caution must be
exercised in titrating these patients (see section 4.2 and 5.2).

Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been performed 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
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. In peri/postnatal studies in rats, an increased gestation time was observed.
Rivastigmine should not be used during pregnancy unless clearly necessary.
Breast-feeding
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is
excreted into human milk. Therefore, women on rivastigmine should not breast-feed.
Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive
performance in rats (see section 5.3). Effects of rivastigmine on human fertility are
not known.

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
Summary of the safety profile
Application site skin reactions (usually mild to moderate application site erythema),
are the most frequent adverse reactions observed with the use of rivastigmine
transdermal patch. The next most common adverse reactions are gastrointestinal in
nature including nausea and vomiting.
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).
Tabulated list of adverse reactions
Table 1 displays the adverse reactions reported in 1670 patients with Alzheimer’s
dementia treated in randomised, double-blind, placebo and active-controlled clinical
studies with rivastigmine transdermal patches for a duration of 24-48 weeks and from
post-marketing data.
Table 1

Infections and infestations
Common:

Urinary tract infection

Metabolism and nutrition disorders
Common:

Anorexia, decreased appetite

Uncommon

Dehydration

Psychiatric disorders
Common:

Anxiety, depression, delirium, agitation

Uncommon

Aggression

Not known:

Hallucinations, restlessness

Nervous system disorders
Common:

Headache, syncope, dizziness

Uncommon

Psychomotor hyperactivity

Very rare:

Extrapyramidal symptoms

Not known:

Worsening of Parkinson’s disease, seizure, tremor, somnolence

Cardiac disorders
Uncommon:

Bradycardia

Not known:

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
(disseminated)

Renal and urinary disorders
Common

Urinary incontinence

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

Rare

Fall
*In a 24-week controlled study in Japanese patients, application site erythema,
application site oedema and application site pruritus were reported as “very
common”.
Description of selected adverse reactions
When doses higher than 13.3 mg/24 h were used in the above-mentioned placebocontrolled study, insomnia, and cardiac failure were observed more frequently than
with 13.3 mg/24 h or placebo, suggesting a dose effect relationship. However, these
events did not occur at a higher frequency with transdermal patches containing
13.3 mg/24 h rivastigmine than with placebo.
The following adverse reactions have only been observed with capsules and oral
solution and not in clinical studies with rivastigmine transdermal patches: malaise,
confusion, sweating increased (common); duodenal ulcers, angina pectoris (rare);
gastrointestinal haemorrhage (very rare); and some cases of severe vomiting were
associated with oesophageal rupture (not known).

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 ≤2.3% in patients treated with Rivastigmine transdermal patches.
The incidence of application site skin reactions leading to discontinuation was higher
in the Asian population with 4.9% and 8.4% in the Chinese and Japanese population
respectively.
In two 24-week double-blind, placebo-controlled clinical trials, skin reactions were
measured at each visit using a skin irritation rating scale. When observed in patients
treated with Rivastigmine transdermal patches, skin irritation was mostly slight or
mild in severity. It was rated as severe in ≤2.2% of patients in these studies and in
≤3.7% of patients treated with Rivastigmine transdermal patches in a Japanese study.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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 24 hours after the overdose.
Cholinergic toxicity has been reported with muscarinic symptoms that are observed
with moderate poisonings such as miosis, flushing, digestive disorders including
abdominal pain, nausea, vomiting and diarrhoea, bradycardia, bronchospasm and
increased bronchial secretions, hyperhidrosis, involuntary urination and/or defecation,
lacrimation, hypotension and salivary hypersecretion.
In more severe cases nicotinic effects might develop such as muscular weakness,
fasciculations, seizures and respiratory arrest with possible fatal outcome.
Additionaly there have been post-marketing cases of dizziness, tremor, headache,
somnolence, confusional state, hypertension, hallucinations and malaise. Overdose
with Rivastigmine transdermal patch resulting from misuse/dosing errors (application
of multiple patches at a time) has been reported in the post-marketing setting and
rarely in clinical trials.
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
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 cholinergic-mediated 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 the inhibition of AChE activity.
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, placebo-controlled core
study and its open-label extension phase and in a 48-week double-blind comparator
study.
24-week placebo-controlled study

Patients involved in the placebo-controlled 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 24-week results for the three
assessment tools are summarised in Table 2.

Table 2

Transdermal
rivastigmine patches

Rivastigmine

Placebo

capsules

9.5 mg/24 h

12 mg/day

N = 251

N = 256

N = 282

(n=248)

(n=253)

(n=281)

Mean baseline ± SD

27.0 ± 10.3

27.9 ± 9.4

28.6 ± 9.9

Mean change at week 24 ± SD

-0.6 ± 6.4

-0.6 ± 6.2

1.0 ± 6.8

ITT-LOCF population
ADAS-Cog

p-value versus placebo

1

1

0.005*

0.003*

(n=248)

(n=253)

(n=278)

3.9 ± 1.20

3.9 ± 1.25

4.2 ± 1.26

ADCS-CGIC
Mean score ± SD
p-value versus placebo

2

2

0.010*

0.009*

(n=247)

(n=254)

(n=281)

Mean baseline ± SD

50.1 ± 16.3

49.3 ± 15.8

49.2 ± 16.0

Mean change at week 24 ± SD

-0.1 ± 9.1

-0.5 ± 9.5

-2.3 ± 9.4

ADCS-ADL

p-value versus placebo

1

0.013*

1

0.039*

* 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 ADCSADL 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 placebo-controlled
study are provided in Table 3. Clinically relevant improvement was defined a priori
as at least 4-point improvement on the ADAS-Cog, no worsening on the ADCSCGIC, and no worsening on the ADCS-ADL.

Table 3

Patients with clinically significant response (%)
Transdermal rivastigmine
patches
9.5 mg/24 h
ITT-LOCF population
At least 4 points

N = 251

Rivastigmine

Placebo

capsules
12 mg/day
N = 256

N = 282

17.4

19.0

10.5

0.037*

0.004*

improvement on ADASCog
with no worsening on
ADCS-CGIC and
ADCS-ADL
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.
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 13.3
mg/24 h transdermal patch against the 9.5 mg/24 h transdermal patch during a 48week 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 9.5 mg/24 h transdermal patch. 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 ADAS-Cog (Alzheimer's
Disease Assessment Scale – Cognitive subscale, a performance-based measure of
cognition) and the ADCS-IADL (Alzheimer's Disease Cooperative Study –
Instrumental Activities of Daily Living) assessing instrumental activities which
include maintaining finances, meal preparation, shopping, ability to orient oneself to
surroundings, ability to be left unattended. The 48-week results for the two
assessment tools are summarised in Table 4.

Table 4

Population/Visit

Transdermal
rivastigmine
patches 15
cm2

Transdermal
rivastigmine
patches 10
cm2

N = 265

N = 271

n

Mean n

Mean

264

34.4

268

34.9

264

38.5

268

39.7

Change

264

4.1

268

4.9

Baseline

265

27.5

271

25.8

Value

265

23.1

271

19.6

Change

265

-4.4

271

-6.2

Transdermal
rivastigmine
patches 15 cm2

Transdermal
rivastigmine
patches 10
cm2

DLSM 95% CI

p-value

ADAS-Cog
Baseline

LOCF

DB-week 48 Value

-0.8

(-2.1,
0.5)

2.2

(0.8, 3.6) 0.002*

0.227

ADCS-IADL
LOCF
Week 48

CI – confidence interval.
DLSM – difference in least square means.
LOCF – Last Observation Carried Forward.
ADAS-cog scores: A negative difference in DLSM indicates greater improvement in Rivastigmine 15
cm2 as compared to Rivastigmine 10 cm2.
ADCS-IADL scores: A positive difference in DLSM indicates greater improvement in Rivastigmine 15
cm2 as compared to Rivastigmine 10 cm2.
N is the number of patients with an assessment at baseline (last assessment in the initial open-label
phase) and with at least 1 post-baseline assessment (for the LOCF).
The DLSM, 95% CI, and p-value are based on an ANCOVA (analysis of covariance) model adjusted for
country and baseline ADAS-cog score. * p<0.05
Source: Study D2340-Table 11-6 and Table 11-7

The European Medicines Agency has waived the obligation to submit the results of
studies with Rivastigmine patch in all subsets of the paediatric population in the
treatment of Alzheimer's dementia (see section 4.2 for information on paediatric use).

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 and 4.9 when
escalating from 4.6 mg/24 h to 9.5 mg/24 h and to 13.3 mg/24 h, respectively. 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, 0.77 for transdermal patches containing 9.5 mg/24 h
rivastigmine and 0.72 for transdermal patches containing 13.3 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
administration 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 population
Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients
treated with transdermal rivastigmine patches.
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.
Following a single 3 mg or 6 mg oral dose, the mean oral clearance of rivastigmine
was approximately 46-63% lower in patients with mild to moderate hepatic
impairment (n=10, Child-Pugh score 5-12, biopsy proven) than in healthy subjects
(n=10).
Renal impairment
No study was conducted with transdermal rivastigmine 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 dose
adjustment is necessary in patients with renal impairment (see section 4.2).

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. The major metabolite NAP226-90 also did not show a 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. In oral studies with 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. Specific dermal studies in pregnant
animals have not been conducted.
Rivastigmine transdermal patches were not phototoxic and considered to be a nonsensitiser. 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.
A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit
study. 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:

Polyester film
Fluoro-coated polyester film

Drug matrix:

Acrylic adhesive
Acrylates copolymer poly(butyl methacrylate-co-methyl
methacrylate)

6.2

Adhesive matrix:

Silicone adhesive

Printing ink:

Black printing ink

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
Erastig 13.3 m/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 under nitrogen
atmosphere.
One sachet contains one transdermal patch.
The sachets are packed in a carton.
Available in packs containing 7, 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
East Sussex
BN22 9AG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 00289/1886

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/06/2015

10

DATE OF REVISION OF THE TEXT
22/06/2015

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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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