ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Prometax 1.5 mg hard capsules
2.
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg.
For a full list of excipients, see section 6.1.
3.
Hard capsules
Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint
“ENA 713 1,5 mg” on body.
4.
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s
disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment
of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made
according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is
available who will regularly monitor intake of the medicinal product by the patient.
Rivastigmine
should be administered twice a day, with morning and evening meals. The capsules should
be swallowed whole.
Initial dose
1.5 mg twice a day.
Dose titration
The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg
twice a day should also be based on good tolerability of the current dose and may be considered after a
minimum of two weeks of treatment at that dose level.
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If
adverse reactions persist, the daily dose should be temporarily
reduced to the previous well-tolerated
dose or the treatment may be discontinued.
2
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be
maintained on their highest well tolerated dose
.
The recommended maximum daily dose is 6 mg twice a
day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists.
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for
patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the
patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be
discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no
longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in
Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in
Parkinson’s disease patients with visual hallucinations (see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.
Re-initiation of therapy
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily.
Dose titration should then be carried out as described above.
Renal and hepatic impairment
Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing
recommendations to titrate according to individual tolerability should be closely followed (see section
5.2).
Patients with severe liver impairment have not been studied (see section 4.3).
Children
Rivastigmine is not recommended for use in children.
The use of this medicinal product is contraindicated in patients with
-
hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients
used in the formulation,
-
severe liver impairment, as it has not been studied in this population.
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the
possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer’s
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia
associated with Parkinson’s disease) have been observed shortly after dose increase. They may
respond to a dose reduction. In other cases, Prometax has been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating
treatment and/or increasing the dose. These adverse reactions occur more commonly in women.
Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors, including rivastigmine,
have been associated with weight loss in these patients. During therapy patient’s weight should be
monitored.
3
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments
or high doses of rivastigmine.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects
(sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients
with active gastric or duodenal ulcers or patients predisposed to these conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or
obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in
treating patients predisposed to such diseases.
The use of rivastigmine in patients with severe dementia of Alzheimer’s disease or associated with
Parkinson’s disease, other types of dementia or other types of memory impairment (e.g. age-related
cognitive decline) has not been investigated and therefore use in these patient populations is not
recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity
of tremor have been observed in patients with dementia associated with Parkinson’s disease (see section
4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to
tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse
reactions.
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 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 rivastigmine. No untoward effects on cardiac conduction were observed
following concomitant administration of digoxin and rivastigmine.
According to its metabolism, metabolic interactions with other medicinal products appear unlikely,
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or
embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity.
In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be
used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human
milk. Therefore, women on rivastigmine should not breast-feed.
4
Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to
use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating
treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the
ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to
continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and
vomiting (23%), especially during titration. Female patients in clinical studies were found to be more
susceptible than male patients to gastrointestinal adverse reactions and weight loss.
The following adverse reactions, listed below in Table 1, have been accumulated in patients with
Alzheimer’s dementia treated with Prometax.
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).
5
Table 1
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Confusion
Insomnia
Depression
Hallucinations
Uncommon
Uncommon
Very rare
Nervous system disorders
Very common
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Common
Common
Common
Uncommon
Rare
Very rare
Cardiac disorders
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Gastric and duodenal ulcers
Gastrointestinal haemorrhage
Pancreatitis
Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.4).
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue disorders
Common
Sweating increased
Rash
Pruritus
Rare
Not known
General disorders and administration
site conditions
Common
Fatigue and asthenia
Malaise
Accidental fall
Uncommon
Investigations
Common
Weight loss
6
Common
Rare
Common
The following additional adverse reactions have been observed with Prometax transdermal patches:
anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s
disease treated with Prometax.
Table 2
Metabolism and nutritional disorders
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Insomnia
Anxiety
Restlessness
Common
Common
Nervous system disorders
Very common
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Common
Common
Common
Common
Common
Common
Uncommon
Cardiac disorders
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
Uncommon
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Common
Common
Common
Skin and subcutaneous tissue disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Fatigue and asthenia
Gait abnormality
Common
7
Common
Common
Very common
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with Prometax in patients with dementia associated with Parkinson’s disease with pre-defined adverse
events that may reflect worsening of parkinsonian symptoms.
Table 3
Pre-defined adverse events that may reflect worsening
of parkinsonian symptoms in patients with dementia
associated with Parkinson’s disease
Prometax
n (%)
Placebo
n (%)
Total patients studied
362 (100)
179 (100)
Total patients with pre-defined AE(s)
99 (27.3)
28 (15.6)
Tremor
37 (10.2)
7 (3.9)
Fall
21 (5.8)
11 (6.1)
Parkinson’s disease (worsening)
12 (3.3)
2 (1.1)
Salivary hypersecretion
5 (1.4)
0
Dyskinesia
5 (1.4)
1 (0.6)
Parkinsonism
8 (2.2)
1 (0.6)
Hypokinesia
1 (0.3)
0
Movement disorder
1 (0.3)
0
Bradykinesia
9 (2.5)
3 (1.7)
Dystonia
3 (0.8)
1 (0.6)
Gait abnormality
5 (1.4)
0
Muscle rigidity
1 (0.3)
0
Balance disorder
3 (0.8)
2 (1.1)
Musculoskeletal stiffness
3 (0.8)
0
Rigors
1 (0.3)
0
Motor dysfunction
1 (0.3)
0
Symptoms
Most cases of accidental overdose 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 occurred in one case; following conservative management the patient fully recovered
within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of
about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine
should be administered 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.
8
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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 and
Parkinson’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 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 rivastigmine was similar
to that of AChE.
Clinical studies in Alzheimer’s dementia
The efficacy of rivastigmine has been established through the use of three independent, domain
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods.
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a
comprehensive global assessment of the patient by the physician incorporating caregiver input), and
the PDS (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 relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
9
The results for clinically relevant responders pooled from two flexible dose studies out of the three
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia,
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10%
improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary definition
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this
indication vary and direct comparisons of results for different therapeutic agents are not valid.
Table 4
Patients with Clinically Significant Response (%)
Intent to Treat
Last Observation Carried
Forward
Response Measure
Rivastigmine
6
–
12 mg
N=473
Placebo
N=472
Rivastigmine
6
–
12 mg
N=379
Placebo
N=444
ADAS-Cog: improvement
of at least 4 points
21***
12
25***
12
CIBIC-Plus: improvement
29***
18
32***
19
PDS: improvement of at
least 10%
26***
17
30***
18
At least 4 points
improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
10*
6
12**
6
*p<0.05, **p<0.01, ***p<0.001
10
Clinical studies in dementia associated with Parkinson’s disease
The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score
of 10–24. Efficacy has been established by the use of two independent scales which were assessed at
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a
measure of cognition, and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study-
Clinician’s Global Impression of Change).
Table 5
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADCS-
CGIC
Prometax
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
Mean change at 24 weeks
± SD
23.8 ± 10.2
2.1 ± 8.2
24.3 ± 10.5
-0.7 ± 7.5
n/a
3.8 ± 1.4
n/a
4.3 ± 1.5
Adjusted treatment
difference
2.88
1
n/a
p-value versus placebo
<0.001
1
0.007
2
ITT - LOCF population
(n=287)
(n=154)
(n=289)
(n=158)
Mean baseline ± SD
Mean change at 24 weeks
± SD
24.0 ± 10.3
2.5 ± 8.4
24.5 ± 10.6
-0.8 ± 7.5
n/a
3.7 ± 1.4
n/a
4.3 ± 1.5
n/a
p-value versus placebo <0.001
1
<0.001
2
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
2
Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
3.54
1
11
Adjusted treatment
difference
Although a treatment effect was demonstrated in the overall study population, the data suggested that a
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients
with visual hallucinations (see Table 6).
Table 6
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADAS-Cog
Prometax
ADAS-Cog
Placebo
Patients with visual
hallucinations
Patients without visual
hallucinations
ITT + RDO population
(n=107)
(n=60)
(n=220)
(n=101)
Mean baseline ± SD
Mean change at 24 weeks
± SD
25.4 ± 9.9
1.0 ± 9.2
27.4 ± 10.4
-2.1 ± 8.3
23.1 ± 10.4
2.6 ± 7.6
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment
difference
4.27
1
2.09
1
p-value versus placebo
0.002
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
(n=87)
(n=44)
(n=237)
(n=115)
Mean baseline ± SD
Mean change at 24 weeks
± SD
32.6 ± 10.4
2.6 ± 9.4
33.7 ± 10.3
-1.8 ± 7.2
20.6 ± 7.9
1.9 ± 7.7
20.7 ± 7.9
-0.2 ± 7.5
2.14
1
p-value versus placebo 0.002
1
0.010
1
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
4.73
1
5.2 Pharmacokinetic properties
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in
approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the
increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute
bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays
absorption (t
max
) by 90 min and lowers C
max
and increases AUC by approximately 30%.
Distribution
Protein binding of rivastigmine is 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.
Metabolism
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour),
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite.
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.
12
Adjusted treatment
difference
Excretion
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of
elimination. Following administration of
14
C-rivastigmine, renal elimination was rapid and essentially
complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There
is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s
disease.
Elderly subjects
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.
Subjects with hepatic impairment
The C
max
of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal impairment
C
max
and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment
compared with healthy subjects; however there were no changes in C
max
and AUC of rivastigmine in
subjects with severe renal impairment.
5.3 Preclinical safety data
Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an
exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human
exposure were achieved in the animal studies 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 10
4
times the maximum clinical
exposure. The
in vivo
micronucleus test was negative.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose,
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the
maximum human dose, a multiple of approximately 6-fold was achieved in animals.
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.
6.
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
13
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or
8 blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/98/092/001-3
EU/1/98/092/014
9.
Date of first authorisation:04.12.1998
Date of latest renewal: 04.12.2008
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
14
1.
Prometax 3.0 mg hard capsules
2.
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3.0 mg.
For a full list of excipients, see section 6.1.
3.
Hard capsules
Off-white to slightly yellow powder in a capsule with orange cap and orange body, with red imprint
“ENA 713 3 mg” on body.
4.
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s
disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment
of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made
according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is
available who will regularly monitor intake of the medicinal product by the patient.
Rivastigmine
should be administered twice a day, with morning and evening meals. The capsules should
be swallowed whole.
Initial dose
1.5 mg twice a day.
Dose titration
The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg
twice a day should also be based on good tolerability of the current dose and may be considered after a
minimum of two weeks of treatment at that dose level.
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If
adverse reactions persist, the daily dose should be temporarily
reduced to the previous well-tolerated
dose or the treatment may be discontinued.
15
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be
maintained on their highest well tolerated dose
.
The recommended maximum daily dose is 6 mg twice a
day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists.
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for
patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the
patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be
discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no
longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in
Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in
Parkinson’s disease patients with visual hallucinations (see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.
Re-initiation of therapy
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily.
Dose titration should then be carried out as described above.
Renal and hepatic impairment
Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing
recommendations to titrate according to individual tolerability should be closely followed (see section
5.2).
Patients with severe liver impairment have not been studied (see section 4.3).
Children
Rivastigmine is not recommended for use in children.
The use of this medicinal product is contraindicated in patients with
-
hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients
used in the formulation,
-
severe liver impairment, as it has not been studied in this population.
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the
possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer’s
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia
associated with Parkinson’s disease) have been observed shortly after dose increase. They may
respond to a dose reduction. In other cases, Prometax has been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating
treatment and/or increasing the dose. These adverse reactions occur more commonly in women.
Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors, including rivastigmine,
have been associated with weight loss in these patients. During therapy patient’s weight should be
monitored.
16
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments
or high doses of rivastigmine.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects
(sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients
with active gastric or duodenal ulcers or patients predisposed to these conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or
obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in
treating patients predisposed to such diseases.
The use of rivastigmine in patients with severe dementia of Alzheimer’s disease or associated with
Parkinson’s disease, other types of dementia or other types of memory impairment (e.g. age-related
cognitive decline) has not been investigated and therefore use in these patient populations is not
recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity
of tremor have been observed in patients with dementia associated with Parkinson’s disease (see section
4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to
tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse
reactions.
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 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 rivastigmine. No untoward effects on cardiac conduction were observed
following concomitant administration of digoxin and rivastigmine.
According to its metabolism, metabolic interactions with other medicinal products appear unlikely,
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or
embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity.
In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be
used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human
milk. Therefore, women on rivastigmine should not breast-feed.
17
Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to
use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating
treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the
ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to
continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and
vomiting (23%), especially during titration. Female patients in clinical studies were found to be more
susceptible than male patients to gastrointestinal adverse reactions and weight loss.
The following adverse reactions, listed below in Table 1, have been accumulated in patients with
Alzheimer’s dementia treated with Prometax.
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).
18
Table 1
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Confusion
Insomnia
Depression
Hallucinations
Uncommon
Uncommon
Very rare
Nervous system disorders
Very common
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Common
Common
Common
Uncommon
Rare
Very rare
Cardiac disorders
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Gastric and duodenal ulcers
Gastrointestinal haemorrhage
Pancreatitis
Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.4).
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue disorders
Common
Sweating increased
Rash
Pruritus
Rare
Not known
General disorders and administration
site conditions
Common
Fatigue and asthenia
Malaise
Accidental fall
Uncommon
Investigations
Common
Weight loss
19
Common
Rare
Common
The following additional adverse reactions have been observed with Prometax transdermal patches:
anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s
disease treated with Prometax.
Table 2
Metabolism and nutritional disorders
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Insomnia
Anxiety
Restlessness
Common
Common
Nervous system disorders
Very common
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Common
Common
Common
Common
Common
Common
Uncommon
Cardiac disorders
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
Uncommon
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Common
Common
Common
Skin and subcutaneous tissue disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Fatigue and asthenia
Gait abnormality
Common
20
Common
Common
Very common
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with Prometax in patients with dementia associated with Parkinson’s disease with pre-defined adverse
events that may reflect worsening of parkinsonian symptoms.
Table 3
Pre-defined adverse events that may reflect worsening
of parkinsonian symptoms in patients with dementia
associated with Parkinson’s disease
Prometax
n (%)
Placebo
n (%)
Total patients studied
362 (100)
179 (100)
Total patients with pre-defined AE(s)
99 (27.3)
28 (15.6)
Tremor
37 (10.2)
7 (3.9)
Fall
21 (5.8)
11 (6.1)
Parkinson’s disease (worsening)
12 (3.3)
2 (1.1)
Salivary hypersecretion
5 (1.4)
0
Dyskinesia
5 (1.4)
1 (0.6)
Parkinsonism
8 (2.2)
1 (0.6)
Hypokinesia
1 (0.3)
0
Movement disorder
1 (0.3)
0
Bradykinesia
9 (2.5)
3 (1.7)
Dystonia
3 (0.8)
1 (0.6)
Gait abnormality
5 (1.4)
0
Muscle rigidity
1 (0.3)
0
Balance disorder
3 (0.8)
2 (1.1)
Musculoskeletal stiffness
3 (0.8)
0
Rigors
1 (0.3)
0
Motor dysfunction
1 (0.3)
0
Symptoms
Most cases of accidental overdose 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 occurred in one case; following conservative management the patient fully recovered
within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of
about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine
should be administered 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.
21
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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 and
Parkinson’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 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 rivastigmine was similar
to that of AChE.
Clinical studies in Alzheimer’s dementia
The efficacy of rivastigmine has been established through the use of three independent, domain
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods.
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a
comprehensive global assessment of the patient by the physician incorporating caregiver input), and
the PDS (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 relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
22
The results for clinically relevant responders pooled from two flexible dose studies out of the three
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia,
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10%
improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary definition
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this
indication vary and direct comparisons of results for different therapeutic agents are not valid.
Table 4
Patients with Clinically Significant Response (%)
Intent to Treat
Last Observation Carried
Forward
Response Measure
Rivastigmine
6
–
12 mg
N=473
Placebo
N=472
Rivastigmine
6
–
12 mg
N=379
Placebo
N=444
ADAS-Cog: improvement
of at least 4 points
21***
12
25***
12
CIBIC-Plus: improvement
29***
18
32***
19
PDS: improvement of at
least 10%
26***
17
30***
18
At least 4 points
improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
10*
6
12**
6
*p<0.05, **p<0.01, ***p<0.001
23
Clinical studies in dementia associated with Parkinson’s disease
The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score
of 10–24. Efficacy has been established by the use of two independent scales which were assessed at
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a
measure of cognition, and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study-
Clinician’s Global Impression of Change).
Table 5
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADCS-
CGIC
Prometax
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
Mean change at 24 weeks
± SD
23.8 ± 10.2
2.1 ± 8.2
24.3 ± 10.5
-0.7 ± 7.5
n/a
3.8 ± 1.4
n/a
4.3 ± 1.5
Adjusted treatment
difference
2.88
1
n/a
p-value versus placebo
<0.001
1
0.007
2
ITT - LOCF population
(n=287)
(n=154)
(n=289)
(n=158)
Mean baseline ± SD
Mean change at 24 weeks
± SD
24.0 ± 10.3
2.5 ± 8.4
24.5 ± 10.6
-0.8 ± 7.5
n/a
3.7 ± 1.4
n/a
4.3 ± 1.5
n/a
p-value versus placebo <0.001
1
<0.001
2
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
2
Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
3.54
1
24
Adjusted treatment
difference
Although a treatment effect was demonstrated in the overall study population, the data suggested that a
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients
with visual hallucinations (see Table 6).
Table 6
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADAS-Cog
Prometax
ADAS-Cog
Placebo
Patients with visual
hallucinations
Patients without visual
hallucinations
ITT + RDO population
(n=107)
(n=60)
(n=220)
(n=101)
Mean baseline ± SD
Mean change at 24 weeks
± SD
25.4 ± 9.9
1.0 ± 9.2
27.4 ± 10.4
-2.1 ± 8.3
23.1 ± 10.4
2.6 ± 7.6
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment
difference
4.27
1
2.09
1
p-value versus placebo
0.002
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
(n=87)
(n=44)
(n=237)
(n=115)
Mean baseline ± SD
Mean change at 24 weeks
± SD
32.6 ± 10.4
2.6 ± 9.4
33.7 ± 10.3
-1.8 ± 7.2
20.6 ± 7.9
1.9 ± 7.7
20.7 ± 7.9
-0.2 ± 7.5
2.14
1
p-value versus placebo 0.002
1
0.010
1
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
4.73
1
5.2 Pharmacokinetic properties
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in
approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the
increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute
bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays
absorption (t
max
) by 90 min and lowers C
max
and increases AUC by approximately 30%.
Distribution
Protein binding of rivastigmine is 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.
Metabolism
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour),
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite.
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.
25
Adjusted treatment
difference
Excretion
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of
elimination. Following administration of
14
C-rivastigmine, renal elimination was rapid and essentially
complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There
is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s
disease.
Elderly subjects
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.
Subjects with hepatic impairment
The C
max
of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal impairment
C
max
and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment
compared with healthy subjects; however there were no changes in C
max
and AUC of rivastigmine in
subjects with severe renal impairment.
5.3 Preclinical safety data
Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an
exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human
exposure were achieved in the animal studies 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 10
4
times the maximum clinical
exposure. The
in vivo
micronucleus test was negative.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose,
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the
maximum human dose, a multiple of approximately 6-fold was achieved in animals.
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.
6.
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
26
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or
8 blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/98/092/004-6
EU/1/98/092/015
9.
Date of first authorisation: 04.12.1998
Date of latest renewal: 04.12.2008
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
27
1.
Prometax 4.5 mg hard capsules
2.
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg.
For a full list of excipients, see section 6.1.
3.
Hard capsules
Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint
“ENA 713 4,5 mg” on body.
4.
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s
disease.
Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatment
of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be made
according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is
available who will regularly monitor intake of the medicinal product by the patient.
Rivastigmine
should be administered twice a day, with morning and evening meals. The capsules should
be swallowed whole.
Initial dose
1.5 mg twice a day.
Dose titration
The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg
twice a day should also be based on good tolerability of the current dose and may be considered after a
minimum of two weeks of treatment at that dose level.
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. If
adverse reactions persist, the daily dose should be temporarily
reduced to the previous well-tolerated
dose or the treatment may be discontinued.
28
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be
maintained on their highest well tolerated dose
.
The recommended maximum daily dose is 6 mg twice a
day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists.
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for
patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the
patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be
discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no
longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in
Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in
Parkinson’s disease patients with visual hallucinations (see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.
Re-initiation of therapy
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily.
Dose titration should then be carried out as described above.
Renal and hepatic impairment
Due to increased exposure in moderate renal and mild to moderate hepatic impairment, dosing
recommendations to titrate according to individual tolerability should be closely followed (see section
5.2).
Patients with severe liver impairment have not been studied (see section 4.3).
Children
Rivastigmine is not recommended for use in children.
The use of this medicinal product is contraindicated in patients with
-
hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients
used in the formulation,
-
severe liver impairment, as it has not been studied in this population.
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the
possibility of adverse reactions (e.g. vomiting).
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer’s
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia
associated with Parkinson’s disease) have been observed shortly after dose increase. They may
respond to a dose reduction. In other cases, Prometax has been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea and vomiting may occur particularly when initiating
treatment and/or increasing the dose. These adverse reactions occur more commonly in women.
Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors, including rivastigmine,
have been associated with weight loss in these patients. During therapy patient’s weight should be
monitored.
29
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments
or high doses of rivastigmine.
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects
(sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients
with active gastric or duodenal ulcers or patients predisposed to these conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or
obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in
treating patients predisposed to such diseases.
The use of rivastigmine in patients with severe dementia of Alzheimer’s disease or associated with
Parkinson’s disease, other types of dementia or other types of memory impairment (e.g. age-related
cognitive decline) has not been investigated and therefore use in these patient populations is not
recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity
of tremor have been observed in patients with dementia associated with Parkinson’s disease (see section
4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to
tremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adverse
reactions.
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 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 rivastigmine. No untoward effects on cardiac conduction were observed
following concomitant administration of digoxin and rivastigmine.
According to its metabolism, metabolic interactions with other medicinal products appear unlikely,
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or
embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity.
In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be
used during pregnancy unless clearly necessary.
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human
milk. Therefore, women on rivastigmine should not breast-feed.
30
Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to
use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating
treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the
ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to
continue driving or operating complex machines should be routinely evaluated by the treating physician.
The most commonly reported adverse reactions are gastrointestinal, including nausea (38%) and
vomiting (23%), especially during titration. Female patients in clinical studies were found to be more
susceptible than male patients to gastrointestinal adverse reactions and weight loss.
The following adverse reactions, listed below in Table 1, have been accumulated in patients with
Alzheimer’s dementia treated with Prometax.
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).
31
Table 1
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Confusion
Insomnia
Depression
Hallucinations
Uncommon
Uncommon
Very rare
Nervous system disorders
Very common
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Common
Common
Common
Uncommon
Rare
Very rare
Cardiac disorders
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Gastric and duodenal ulcers
Gastrointestinal haemorrhage
Pancreatitis
Some cases of severe vomiting were associated with
oesophageal rupture (see section 4.4).
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue disorders
Common
Sweating increased
Rash
Pruritus
Rare
Not known
General disorders and administration
site conditions
Common
Fatigue and asthenia
Malaise
Accidental fall
Uncommon
Investigations
Common
Weight loss
32
Common
Rare
Common
The following additional adverse reactions have been observed with Prometax transdermal patches:
anxiety, delirium, pyrexia (common).
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s
disease treated with Prometax.
Table 2
Metabolism and nutritional disorders
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Insomnia
Anxiety
Restlessness
Common
Common
Nervous system disorders
Very common
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Common
Common
Common
Common
Common
Common
Uncommon
Cardiac disorders
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
Uncommon
Gastrointestinal disorders
Very common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Common
Common
Common
Skin and subcutaneous tissue disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Fatigue and asthenia
Gait abnormality
Common
33
Common
Common
Very common
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with Prometax in patients with dementia associated with Parkinson’s disease with pre-defined adverse
events that may reflect worsening of parkinsonian symptoms.
Table 3
Pre-defined adverse events that may reflect worsening
of parkinsonian symptoms in patients with dementia
associated with Parkinson’s disease
Prometax
n (%)
Placebo
n (%)
Total patients studied
362 (100)
179 (100)
Total patients with pre-defined AE(s)
99 (27.3)
28 (15.6)
Tremor
37 (10.2)
7 (3.9)
Fall
21 (5.8)
11 (6.1)
Parkinson’s disease (worsening)
12 (3.3)
2 (1.1)
Salivary hypersecretion
5 (1.4)
0
Dyskinesia
5 (1.4)
1 (0.6)
Parkinsonism
8 (2.2)
1 (0.6)
Hypokinesia
1 (0.3)
0
Movement disorder
1 (0.3)
0
Bradykinesia
9 (2.5)
3 (1.7)
Dystonia
3 (0.8)
1 (0.6)
Gait abnormality
5 (1.4)
0
Muscle rigidity
1 (0.3)
0
Balance disorder
3 (0.8)
2 (1.1)
Musculoskeletal stiffness
3 (0.8)
0
Rigors
1 (0.3)
0
Motor dysfunction
1 (0.3)
0
Symptoms
Most cases of accidental overdose 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 occurred in one case; following conservative management the patient fully recovered
within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of
about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine
should be administered 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.
34
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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 and
Parkinson’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 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 rivastigmine was similar
to that of AChE.
Clinical studies in Alzheimer’s dementia
The efficacy of rivastigmine has been established through the use of three independent, domain
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods.
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a
comprehensive global assessment of the patient by the physician incorporating caregiver input), and
the PDS (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 relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
35
The results for clinically relevant responders pooled from two flexible dose studies out of the three
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia,
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10%
improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary definition
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this
indication vary and direct comparisons of results for different therapeutic agents are not valid.
Table 4
Patients with Clinically Significant Response (%)
Intent to Treat
Last Observation Carried
Forward
Response Measure
Rivastigmine
6
–
12 mg
N=473
Placebo
N=472
Rivastigmine
6
–
12 mg
N=379
Placebo
N=444
ADAS-Cog: improvement
of at least 4 points
21***
12
25***
12
CIBIC-Plus: improvement
29***
18
32***
19
PDS: improvement of at
least 10%
26***
17
30***
18
At least 4 points
improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
10*
6
12**
6
*p<0.05, **p<0.01, ***p<0.001
36
Clinical studies in dementia associated with Parkinson’s disease
The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score
of 10–24. Efficacy has been established by the use of two independent scales which were assessed at
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a
measure of cognition, and the global measure ADCS-CGIC (Alzheimer’s Disease Cooperative Study-
Clinician’s Global Impression of Change).
Table 5
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADCS-
CGIC
Prometax
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
Mean change at 24 weeks
± SD
23.8 ± 10.2
2.1 ± 8.2
24.3 ± 10.5
-0.7 ± 7.5
n/a
3.8 ± 1.4
n/a
4.3 ± 1.5
Adjusted treatment
difference
2.88
1
n/a
p-value versus placebo
<0.001
1
0.007
2
ITT - LOCF population
(n=287)
(n=154)
(n=289)
(n=158)
Mean baseline ± SD
Mean change at 24 weeks
± SD
24.0 ± 10.3
2.5 ± 8.4
24.5 ± 10.6
-0.8 ± 7.5
n/a
3.7 ± 1.4
n/a
4.3 ± 1.5
n/a
p-value versus placebo <0.001
1
<0.001
2
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
2
Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward
3.54
1
37
Adjusted treatment
difference
Although a treatment effect was demonstrated in the overall study population, the data suggested that a
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients
with visual hallucinations (see Table 6).
Table 6
Dementia associated with
Parkinson’s Disease
ADAS-Cog
Prometax
ADAS-Cog
Placebo
ADAS-Cog
Prometax
ADAS-Cog
Placebo
Patients with visual
hallucinations
Patients without visual
hallucinations
ITT + RDO population
(n=107)
(n=60)
(n=220)
(n=101)
Mean baseline ± SD
Mean change at 24 weeks
± SD
25.4 ± 9.9
1.0 ± 9.2
27.4 ± 10.4
-2.1 ± 8.3
23.1 ± 10.4
2.6 ± 7.6
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment
difference
4.27
1
2.09
1
p-value versus placebo
0.002
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
(n=87)
(n=44)
(n=237)
(n=115)
Mean baseline ± SD
Mean change at 24 weeks
± SD
32.6 ± 10.4
2.6 ± 9.4
33.7 ± 10.3
-1.8 ± 7.2
20.6 ± 7.9
1.9 ± 7.7
20.7 ± 7.9
-0.2 ± 7.5
2.14
1
p-value versus placebo 0.002
1
0.010
1
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A
positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
4.73
1
5.2 Pharmacokinetic properties
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in
approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the
increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute
bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays
absorption (t
max
) by 90 min and lowers C
max
and increases AUC by approximately 30%.
Distribution
Protein binding of rivastigmine is 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.
Metabolism
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour),
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite.
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.
38
Adjusted treatment
difference
Excretion
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route of
elimination. Following administration of
14
C-rivastigmine, renal elimination was rapid and essentially
complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. There
is no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s
disease.
Elderly subjects
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.
Subjects with hepatic impairment
The C
max
of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.
Subjects with renal impairment
C
max
and AUC of rivastigmine were more than twice as high in subjects with moderate renal impairment
compared with healthy subjects; however there were no changes in C
max
and AUC of rivastigmine in
subjects with severe renal impairment.
5.3 Preclinical safety data
Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with an
exaggerated pharmacological action. No target organ toxicity was observed. No safety margins to human
exposure were achieved in the animal studies 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 10
4
times the maximum clinical
exposure. The
in vivo
micronucleus test was negative.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose,
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the
maximum human dose, a multiple of approximately 6-fold was achieved in animals.
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.
6.
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
39
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or
8 blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
8.
EU/1/98/092/007-9
EU/1/98/092/016
9.
Date of first authorisation: 04.12.1998
Date of latest renewal: 04.12.2008
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
40
1.
6. FURTHER INFORMATION
What Prometax contains
-
The active substance is rivastigmine.
-
Prometax 4.6 mg/24 h transdermal patches: Each patch releases 4.6 mg of rivastigmine
per 24 hours is 5 cm
2
and contains 9 mg of rivastigmine.
-
Prometax 9.5 mg/24 h transdermal patches: Each patch releases 9.5 mg of rivastigmine
per 24 hours is 10 cm
2
and contains 18 mg of rivastigmine.
-
The other ingredients are: polyethylene terephthalate film lacquered, alpha-tocopherol,
poly(butylmethacrylate, methyl-methacrylate), acrylic copolymer, silicone oil, dimethicone,
polyester film fluoropolymer-coated.
What Prometax looks like and contents of the pack
Each transdermal patch is a thin patch consisting of three layers. The outer layer is beige and labelled
with the following:
-
“Prometax”, “4.6 mg/24 h” and “AMCX”,
-
“Prometax”, “9.5 mg/24 h” and “BHDI”.
One transdermal patch is sealed in one sachet. The patches are available in packs containing 7 or
30 sachets and in multipacks containing 60 (2x 30) or 90 (3x 30) sachets. Not all pack sizes may be
marketed in your country.
Marketing Authorisation Holder
Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex, RH12 5AB
United Kingdom
Manufacturer
Novartis Pharma GmbH
Roonstraße 25
D-90429 Nuremberg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Novartis Pharma N.V.
Tél/Tel: +32 2 246 16 11
Luxembourg/Luxemburg
Novartis Pharma GmbH
Tél/Tel: +49 911 273 0
България
Novartis Pharma Services Inc.
Тел.: +359 2 489 98 28
Magyarország
Novartis Hungária Kft. Pharma
Tel.: +36 1 457 65 00
Česká republika
Novartis s.r.o.
Tel: +420 225 775 111
Malta
Novartis Pharma Services Inc.
Tel: +356 2298 3217
Danmark
Novartis Healthcare A/S
Tlf: +45 39 16 84 00
Nederland
Novartis Pharma B.V.
Tel: +31 26 37 82 111
150
Deutschland
Novartis Pharma GmbH
Tel: +49 911 273 0
Norge
Novartis Norge AS
Tlf: +47 23 05 20 00
Eesti
Novartis Pharma Services Inc.
Tel: +372 66 30 810
Österreich
Novartis Pharma GmbH
Tel: +43 1 86 6570
Ελλάδα
Novartis (Hellas) A.E.B.E.
Τηλ: +30 210 281 17 12
Polska
Novartis Poland Sp. z o.o.
Tel.: +48 22 550 8888
España
Laboratorios Dr. Esteve, S.A.
Tel: +34 93 446 60 00
Portugal
MediBIAL, Produtos Médicos e Farmacêuticos,
S.A.
Tel: +351 22 986 6100
France
Novartis Pharma S.A.S.
Tél: +33 1 55 47 66 00
România
Novartis Pharma Services Inc.
Tel: +40 21 31299 01
Ireland
Novartis Ireland Limited
Tel: +353 1 260 12 55
Slovenija
Novartis Pharma Services Inc.
Tel: +386 1 300 75 50
Ísland
Vistor hf.
Sími: +354 535 7000
Slovenská republika
Novartis Slovakia s.r.o.
Tel: +421 2 5542 5439
Italia
Biofutura Pharma S.p.A.
Tel: +39 02 8027171
Suomi/Finland
Novartis Finland Oy
Puh/Tel: +358 (0)10 6133 200
Κύπρος
Novartis Pharma Services Inc.
Τηλ: +357 22 690 690
Sverige
Novartis Sverige AB
Tel: +46 8 732 32 00
Latvija
Novartis Pharma Services Inc.
Tel: +371 67 887 070
United Kingdom
Novartis Pharmaceuticals UK Ltd.
Tel: +44 1276 698370
Lietuva
Novartis Pharma Services Inc.
Tel: +370 5 269 16 50
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
151
Source: European Medicines Agency
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