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VOLEZE 13.3 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
Voleze 13.3 mg/24 h transdermal patch

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each transdermal patch releases 13.3 mg rivastigmine per 24 hours.
Each transdermal patch of 15 cm2 contains 27 mg rivastigmine.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Transdermal patch.
Round-shaped three-layer matrix transdermal patches.
The outside of the backing layer is translucent, white and imprinted with black
printing ink as follows:
“Rivastigmine, 13.3 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
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*

* 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 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








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 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:
• 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.
The 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.
Breastfeeding
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 machines. 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
rivastigmine transdermal 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 rivastigmine oral formulations.
Management:
As rivastigmine has a plasma half-life of about 3.4 hours and aduration 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 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 performancebased measure of cognition) and the ADCS-CGIC (Alzheimer’s Disease
Cooperative Study – Clinician’s Global Impression of Change, a
comprehensive global assessment of the patient by the physician incorporating
caregiver input), and the ADCS-ADL (Alzheimer’s Disease Cooperative
Study – Activities of Daily Living, a caregiver-rated assessment of the
activities of daily living including personal hygiene, feeding, dressing,
household chores such as shopping, retention of ability to orient oneself to
surroundings as well as involvement in activities related to finances). The 24week results for the three assessment tools are summarised in Table 2.
Table 2

ITT-LOCF population
ADAS-Cog

Rivastigmine
transdermal 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

N = 282

ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward
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.
1

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

ITT-LOCF population
At least 4 points
improvement on ADASCog
with no worsening on
ADCS-CGIC and ADCSADL

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

0.037*

Placebo

N = 282
10.5

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 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 performancebased 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

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

Rivastigmine
patch 15 cm2
(n = 265)
n
Mean

Rivastigmine
patch 10 cm2
(n = 271)
n
Mean

Rivastigmine
patch 15 cm2

Rivastigmine
patch 10 cm2

DLSM

95% CI

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

2.2

(0.8, 3.6)

0.002*

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.
ADAS-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 DSLM, 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 rivastigmine 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 overproportionally by a factor of 2.6 and 4.9 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 rivastigmine 4.6
mg/24 h transdermal patches, 0.77 for rivastigmine 9.5 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 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 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
Film:
Drug matrix:
Adhesive matrix:
Printing ink:

Polyester film
Fluoro-coated polyester film
Acrylic adhesive, Acrylates copolymer poly(butyl
methacrylat-co-methyl methacrylat) (80:20)
Silicone adhesive
Black printing ink

6.2

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

6.3

Shelf life
2 years

6.4

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

6.5

Nature and contents of container
Primary packaging material
Voleze 13.3 mg/24 h transdermal patches are individually packed in child-resistant
heat-sealed sachets made of a paper/PET/aluminium/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)
PL20046/0278

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/10/2014

10

DATE OF REVISION OF THE TEXT
28/04/2016

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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