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VOLEZE 4.6 MG/24 H TRANSDERMAL PATCH

Active substance(s): RIVASTIGMINE

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Voleze 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.
Voleze 4.6 mg/24 h transdermal patch 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
Voleze 4.6 mg/24 h
Voleze 9.5 mg/24 h
Voleze 13.3 mg/24 h

Rivastigmine in vivo
release rates per 24 h
4.6 mg
9.5 mg
13.3 mg

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, this dose 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 maintenance 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 Voleze 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. 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).
Paediatric population
There is no relevant use of Voleze 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
increased exposure in these populations as observed with the oral forms, dosing
recommendations to titrate accordingly 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).
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:
• 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.

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 three
days, it should be re-initiated with 4.6 mg/24 h.
Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence
of torsade de pointes, predominantly in patients with risk factors. Caution is advised
in patients at higher risk of developing torsade de pointes; for example, those with
uncompensated heart failure, recent myocardial infarction, bradyarrhythmias, a
predisposition to hypokalaemia or hypomagnesaemia, or concomitant use with
medicinal products known to induce QT prolongation and/or torsade de pointes (see
sections 4.5 and 4.8)

Misuse of the medicinal product and dosing errors resulting in overdose
Misuse of the medicinal product and dosing errors with Voleze 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 Voleze 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 Voleze transdermal patches.
Other adverse reactions
Care must be taken when prescribing Voleze 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 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 Voleze 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 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.

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 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
breastfeed.
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 reported in 854 patients with
Alzheimer’s dementia treated in randomised, double-blind, placebo and
active-controlled clinical studies with rivastigmine transdermal patches or 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, nightmares
Nervous system disorders
Common:
Headache, syncope, dizziness
Uncommon
Psychomotor hyperactivity
Very rare:
Extrapyramidal symptoms
Not known:
Worsening of Parkinson`s disease, 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:
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
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 Voleze13.3 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 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.
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 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. 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.
Management
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; 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 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

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
* p≤0.05 versus placebo

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

ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward

N = 282

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
ADCS-CGIC and ADCSADL

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

0.037*

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.
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.

Placebo

N = 282
10.5

Table 4
Transdermal Transdermal
rivastigmine
rivastigmine
patches 15cm2 patches 10cm2

Population
/Visit

ADAS-Cog

DBweek
48

N=265

N=271

n

Mean

n

Mean

Baseline

265

34.4

268

34.9

Value

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 15cm2

Transdermal
rivastigmine
patches 10cm2

DLS
M

95% CI

p-value

-0.8

(-2.1,0.5)

0.227

2.2

(0.8, 3.6)

0.002*

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
transdermal rivastigmine patches 15cm2 as compared to transdermal rivastigmine
10cm2.
ADCS-IADL scores: A positive difference in DLSM indicates greater improvement
in transdermal rivastigmine 15cm2 patches as compared to transdermal rivastigmine
patches 10cm2.
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 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 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% (AUC024h) 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 NAP22690 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
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.

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:

Polyester film
Fluoro-coated polyester film

6.2

Drug matrix:

Acrylic adhesive , Acrylates copolymer poly(butyl
methacrylat-co-methyl methacrylat)

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
Primary packaging material
Voleze 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 unused medicinal product or waste material should be disposed of in
accordance with local requirements.

7

MARKETING AUTHORISATION HOLDER
Focus Pharmaceuticals Ltd
Capital House, 1st Floor,
85 King William Street,
London EC4N 7BL,
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL20046/0101

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
01/03/2013

10

DATE OF REVISION OF THE TEXT
28/04/2016

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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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