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ALZEST 4.6 MG/24 H TRANSDERMAL PATCH

Active substance(s): RIVASTIGMINE / RIVASTIGMINE / RIVASTIGMINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Alzest 4.6 mg/24 h Transdermal Patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch releases 4.6 mg of rivastigmine per 24 hours. Each
transdermal patch of 4.6 cm2 contains 6.9 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. The outside of the
backing layer is tan coloured.
Each patch is printed in orange with “RIV-TDS 4.6 mg/24 h”.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.

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
Alzest 4.6 mg/24 h
4.6 mg
Alzest 9.5 mg/24 h
9.5 mg
Rivastigmine 13.3 mg/24 h*
13.3 mg
*The 13.3 mg/24 h dose strength cannot be achieved with this product. For conditions
where this strength should be used, please refer to other rivastigmine products for
which transdermal patches of the 13.3 mg/24 h strength 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 rivastigmine capsules or oral solution can be
switched to Alzest 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 rivastigmine 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: No dose adjustment is necessary for patients with hepatic
impairment. However, due to increased exposure in these populations as
observed with the oral forms, dosing recommendations to titrate according to
individual tolerability should be closely followed as patients with clinically
significant hepatic impairment might experience more adverse reactions. Patients
with severe hepatic impairment have not been studied (see sections 4.4 and 5.2).



Renal impairment: No dose adjustment is necessary for patients with renal
impairment. However, due to increased exposure in these populations as
observed with the oral forms, dosing recommendations to titrate according to
individual tolerability should be closely followed as patients with clinically
significant renal impairment might experience more adverse reactions (see
sections 4.4 and 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 rivastigmine 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
rivastigmine 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 rivastigmine transdermal patches.
Other adverse reactions
Care must be taken when prescribing Alzest transdermal patches:
• to patients with sick sinus syndrome or conduction defects (sino-atrial block, atrioventricular 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 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).
Other warnings and precautions
Rivastigmine may exacerbate or induce extrapyramidal symptoms.
Contact with the eyes should be avoided after handling Alzest 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
• 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 might
experience more adverse reactions (see section 4.2 and 5.2). Consider using the
4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.
• Renal impairment: Patients with clinically significant renal impairment might
experience more adverse reactions (see sections 4.2 and 5.2). Consider using the
4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.

4.5

Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been performed with rivastigmine transdermal
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
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 effects on fertility or embryofoetal development were observed in rats and rabbits,
except at doses related to maternal toxicity.

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 in 854 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 postmarketing 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 desease, seizure
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 cutaneous
hypersensitivity reactions
Renal and urinary disorders
Common
Urinary incontinence
General disorders and administration site conditions

Common

Rare

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
Fall

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 rivastigmine 13.3 mg/24 h
transdermal patches than with placebo.
The following adverse reactions have only been observed with rivastigmine capsules
and oral solution and not in clinical studies with rivastigmine transdermal patches:
somnolence, malaise, tremor, 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 a 24-week double-blind, placebo-controlled clinical trial, 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 the 24-week doubleblind 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.
In a 48-week active-controlled clinical trial, cases of skin irritation were captured as
patient or caregiver reported adverse reactions. The most commonly reported skin
irritation events during the first 24 weeks of the double-blind period with rivastigmine
13.3 mg/24 h transdermal patches and rivastigmine 9.5 mg/24 h transdermal patches,
respectively were application site erythema (5.7% vs 4.6%) and application site
pruritus (3.6% vs 2.8%). The percentages decreased in both rivastigmine
13.3 mg/24 h transdermal patch and rivastigmine 9.5 mg/24 h transdermal patch
treatment groups over time (>24 weeks): application site erythema (0.8% vs. 1.6%)
and application site pruritus (0.4% vs. 1.2%), respectively. Application site pruritus
led to discontinuation in 1.1% of the patients from each of the treatment groups
during the total 48-week double-blind treatment phase. Application site reactions
were mostly mild to moderate in severity and were rated as severe in less than 2% of
patients.
A direct comparison of the rate of skin irritation events reported in each of these
studies cannot be made due to the difference in data collection methods employed.

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, website: 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. 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
rivastigmine transdermal patch 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 rivastigmine oral 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 Alzest transdermal 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; anti-dementia drugs;
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 rivastigmine transdermal 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

ITT-LOCF population

Rivastigmine
transdermal
patches
9.5 mg/24 h

Rivastigmine
capsules
12 mg/day
N = 256

Placebo
N = 282

(n=248)

(n=253)

(n=281)

27.0 ± 10.3

27.9 ± 9.4

28.6 ± 9.9

-0.6 ± 6.4

-0.6 ± 6.2

1.0 ± 6.8

0.005*1

0.003*1

ADAS-Cog

Mean baseline ± SD
Mean change at week 24 ±
SD
p-value versus placebo
ADCS-CGIC

Mean score ± SD
p-value versus placebo

(n=248)

(n=253)

(n=278)

3.9 ± 1.20

3.9 ±± 1.25

4.2 ± 1.26

0.010*2

0.009*2

(n=247)

(n=254)

ADCS-ADL

50.1 ± 16.3

Mean baseline ± SD
Mean change at week 24 ±
SD
p-value versus placebo

(n=281)

49.3 ± 15.8 49.2 ± 16.0

-0.1 ± 9.1

-0.5 ± 9.5

0.013*1

0.039*1

-2.3 ± 9.4

* 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 placebo-controlled
study are provided in Table 3. 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 3

ITT-LOCF population
At least 4 points
improvement on ADASCog with no worsening
on ADCSCGIC and
ADCS-ADL
p-value versus placebo

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

0.037*

0.004*

* 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
48-week double-blind treatment phase in Alzheimer’s disease patients who
demonstrated functional and cognitive decline after an initial 24-48 week open-label
treatment phase while on a maintenance dose of 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
Rivastigmine
patch 15 cm2
N = 265

Rivastigmine
patch 10 cm2
N = 271

Rivastigmine patch
15 cm2

Rivastigmine
patch
10 cm2

n

Mean

n

Mean

DLSM

95% Cl

p-value

Baseline
Value
Change

264
264
264

34.4
38.5
4.1

268
268
268

34.9
39.7
4.9

-0.8

(-2.1, 0.5)

0.227

Baseline
Value
Change

265
265
265

27.5
23.1
-4.4

271
271
271

25.8
19.6
-6.2

Population/Visit

ADAS-Cog
LOCF
DB-week 48
ADCS-IADL
LOCF
Week 48

2.2
(0.8, 3.6)
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 openlabel 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 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

0.002*

Absorption of rivastigmine from rivastigmine transdermal patches is slow. After the
first dose, detectable plasma concentrations are observed after a lag time of 0.51 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 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 rivastigmine 4.6 mg/24 h transdermal patches, 0.77 for rivastigmine 9.5 mg/24 h
transdermal patches and 0.72 for rivastigmine 13.3 mg/24 h transdermal patches, 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 steadystate 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 litres/h
after a 0.2 mg intravenous dose and decreased to 70 litres/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 rivastigmine transdermal patches.
Hepatic impairment
No study was conducted with rivastigmine 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.
Renal impairment
No study was conducted with rivastigmine transdermal 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 rivastigmine 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
section 4.4).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Matrix:
- poly [(2-ethylhexyl)acrylate, vinylacetate]
- medium molecular weight polyisobutene
- high molecular weight polyisobutene
- silica, colloidal anhydrous
- paraffin, light liquid
Backing liner:

- polyethylene/thermoplastic resin/aluminium coated polyester film
Release liner:
- polyester film, fluoropolymer-coated
Orange 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
3 years

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
Keep the transdermal patch in the sachet until use.

6.5

Nature and contents of container
Each child-resistant sachet is made of a paper / polyethylene terephthalate /
aluminium / polyacrylnitrile multilaminated material. One sachet contains one
transdermal patch.
Each transdermal patch is protected by a cover sheet made of siliconised polyethylene
terephthalate film.
Available in packs containing 7, 30 or 42 sachets and in multipacks containing 60, 84
or 90 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
Dr. Reddy’s Laboratories (UK) Ltd.
6 Riverview Road
Beverley
East Yorkshire
HU17 0LD
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 08553/0506

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
03/03/2014

10

DATE OF REVISION OF THE TEXT
09/09/2014

Expand Transcript

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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