ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rivastigmine Teva 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 capsule
White cap imprinted with “R” & white body imprinted with “1.5”
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 the 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, rivastigmine 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 has 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 rivastigmine.
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).
Table 1
*
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional
disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Common
Confusion
Uncommon
Insomnia
Uncommon
Depression
Very rare
Hallucinations
Nervous system disorders
Very common
Dizziness
Common
Headache
Common
Somnolence
Common
Tremor
Uncommon
Syncope
Rare
Seizures
Very rare
Extrapyramidal symptoms (including worsening of
Parkinson's disease)
Cardiac disorders
Rare
Angina pectoris
5
Very rare
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular Disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Very common
Diarrhoea
Common
Abdominal pain and dyspepsia
Rare
Gastric and duodenal ulcers
Very rare
Gastrointestinal haemorrhage
Very rare
Pancreatitis
Not known
Some cases of severe vomiting were associated with
oesphageal rupture (see section 4.4).
Hepato-biliary disorders
Uncommon
Elivated liver function tests
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Rare
Rash
Not known
Pruritus
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Malaise
Uncommon
Accidental fall
Investigations
Common
Weight loss
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s
disease treated with rivastigmine.
Table 2
Metabolism and nutritional
disorders
Common
Anorexia
Common
Dehydration
Psychiatric disorders
Common
Insomnia
Common
Anxiety
6
Common
Restlessness
Nervous system disorders
Very common
Tremor
Common
Dizziness
Common
Somnolence
Common
Headache
Common
Worsening of Parkinson’s disease
Common
Bradykinesia
Common
Dyskinesia
Uncommon
Dystonia
Cardiac disorders
Common
Bradycardia
Uncommon
Atrial fibrillation
Uncommon
Atrioventricular block
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Common
Diarrhoea
Common
Abdominal pain and dyspesia
Common
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Muscoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with rivastigmine 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
Rivastigmine
Placebo
n (%)
n (%)
7
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 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.
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
9
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
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
Rivastigmine
ADAS-Cog
Placebo
ADCS-CGIC
Rivastigmine
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
23.8±10.2
24.3±10.5
n/a
n/a
Mean change at 24 weeks
± SD
2.1±8.2
-0.7±7.5
3.8±1.4
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
24.0±10.3
24.5±10.6
n/a
n/a
Mean change at 24 weeks
± SD
2.5±8.4
-0.8±7.5
3.7±1.4
4.3±1.5
Adjusted treatment
difference
3.54
1
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
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).
10
Table 6
Dementia associated
with Parkinson's Disease
ADAS-Cog
Rivastigmine
ADAS-Cog
Placebo
ADAS-Cog
Rivastigmine
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
25.4±9.9
27.4±10.4
23.1±10.4
22.5±10.1
Mean change at 24 weeks
± SD
1.0±9.2
-2.1±8.3
2.6±7.6
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
32.6±10.4
33.7±10.3
20.6±7.9
20.7±7.9
Mean change at 24 weeks
± SD
2.6±9.4
-1.8±7.2
1.9±7.7
-0.2±7.5
Adjusted treatment
difference
4.73
1
2.14
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
0.002
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.
11
p-value versus placebo
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
Capsule contents
Microcrystalline cellulose
Hypromellose
Colloidal silicon dioxide
Magnesium stearate
Capsule shell
Titanium dioxide (E171)
Gelatin
Ink used for imprinting - Black S-1-17822/S-1-17823:
Shellac glaze-45%
12
Iron oxide black
Ammonium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5
Nature and contents of container
-
HDPE tablet container with a polypropylene cap and induction seal: 250 capsules
-
28, 56 or 112 capsules in transparent PVC/Alu push through blisters
-
50 x 1 capsules in PVC/Alu push through perforated unit dose blisters
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
8.
9.
Detailed information on this product is available on the website of the European Medicines Agency
13
1.
Rivastigmine Teva 3 mg hard capsules
2.
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg
For a full list of excipients, see section 6.1.
3.
Hard capsule
Flesh colour cap imprinted with “R” & flesh color body imprinted with “3”
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 the 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.
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
14
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, rivastigmine 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.
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).
15
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
reccommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or
severity of tremor has 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 reccomemended 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
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.
16
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 rivastigmine.
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).
Table 1
*
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional
disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Common
Confusion
Uncommon
Insomnia
Uncommon
Depression
Very rare
Hallucinations
Nervous system disorders
Very common
Dizziness
Common
Headache
Common
Somnolence
Common
Tremor
Uncommon
Syncope
Rare
Seizures
Very rare
Extrapyramidal symptoms (including worsening of
Parkinson's disease)
Cardiac disorders
Rare
Angina pectoris
Very rare
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular Disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
17
Very common
Vomiting
Very common
Diarrhoea
Common
Abdominal pain and dyspepsia
Rare
Gastric and duodenal ulcers
Very rare
Gastrointestinal haemorrhage
Very rare
Pancreatitis
Not known
Some cases of severe vomiting were associated with
oesphageal rupture (see section 4.4).
Hepato-biliary disorders
Uncommon
Elivated liver function tests
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Rare
Rash
Not known
Pruritus
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Malaise
Uncommon
Accidental fall
Investigations
Common
Weight loss
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s
disease treated with rivastigmine.
Table 2
Metabolism and nutritional
disorders
Common
Anorexia
Common
Dehydration
Psychiatric disorders
Common
Insomnia
Common
Anxiety
Common
Restlessness
Nervous system disorders
Very common
Tremor
Common
Dizziness
Common
Somnolence
18
Common
Headache
Common
Worsening of Parkinson’s disease
Common
Bradykinesia
Common
Dyskinesia
Uncommon
Dystonia
Cardiac disorders
Common
Bradycardia
Uncommon
Atrial fibrillation
Uncommon
Atrioventricular block
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Common
Diarrhoea
Common
Abdominal pain and dyspesia
Common
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Muscoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with rivastigmine 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
Rivastigmine
Placebo
n (%)
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)
19
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 overdosage 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 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
events 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.
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.
20
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.
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
21
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
Rivastigmine
ADAS-Cog
Placebo
ADCS-CGIC
Rivastigmine
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
23.8±10.2
24.3±10.5
n/a
n/a
Mean change at 24 weeks
± SD
2.1±8.2
-0.7±7.5
3.8±1.4
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
24.0±10.3
24.5±10.6
n/a
n/a
Mean change at 24 weeks
± SD
2.5±8.4
-0.8±7.5
3.7±1.4
4.3±1.5
Adjusted treatment
difference
3.54
1
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
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
Rivastigmine
ADAS-Cog
Placebo
ADAS-Cog
Rivastigmine
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
25.4±9.9
27.4±10.4
23.1±10.4
22.5±10.1
Mean change at 24 weeks
± SD
1.0±9.2
-2.1±8.3
2.6±7.6
0.1±6.9
Adjusted treatment
difference
4.27
1
2.09
1
22
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
32.6±10.4
33.7±10.3
20.6±7.9
20.7±7.9
Mean change at 24 weeks
± SD
2.6±9.4
-1.8±7.2
1.9±7.7
-0.2±7.5
Adjusted treatment
difference
4.73
1
2.14
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
0.002
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.
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.
23
p-value versus placebo
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
Capsule contents
Microcrystalline cellulose
Hypromellose
Colloidal silicon dioxide
Magnesium stearate
Capsule shell
Red iron oxide (E 172)
Yellow iron oxide (E 172)
Titanium dioxide (E 171)
Gelatin
Ink used for imprinting - Black S-1-17822/S-1-17823
Shellac glaze-45%
Iron oxide black
Ammonium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
24
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5
Nature and contents of container
-
HDPE tablet container with a polypropylene cap and induction seal: 250 capsules
-
28, 56 or 112 capsules in transparent PVC/Alu push through blisters
-
50 x 1 capsules in PVC/Alu push through perforated unit dose blisters
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
8.
9.
Detailed information on this product is available on the website of the European Medicines Agency
25
1.
Rivastigmine Teva 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 capsule
Orange colour cap imprinted with “R” & orange color body imprinted with “4.5”
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 the 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.
26
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, rivastigmine 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.
27
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 the use in these patient populations is not
reccommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or
severity of tremor has 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 reccommended 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
28
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 or use machinges. 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 rivastigmine.
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)
Table 1
*
Infections and infestations
Very rare
Urinary infection
Metabolism and nutritional
disorders
Very common
Anorexia
Psychiatric disorders
Common
Agitation
Common
Confusion
Uncommon
Insomnia
Uncommon
Depression
Very rare
Hallucinations
Nervous system disorders
Very common
Dizziness
Common
Headache
Common
Somnolence
Common
Tremor
Uncommon
Syncope
Rare
Seizures
Very rare
Extrapyramidal symptoms (including worsening of
Parkinson's disease)
Cardiac disorders
Rare
Angina pectoris
29
Very rare
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block,
atrial fibrillation and tachycardia)
Vascular Disorders
Very rare
Hypertension
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Very common
Diarrhoea
Common
Abdominal pain and dyspepsia
Rare
Gastric and duodenal ulcers
Very rare
Gastrointestinal haemorrhage
Very rare
Pancreatitis
Not known
Some cases of severe vomiting were associated with
oesphageal rupture (see section 4.4).
Hepato-biliary disorders
Uncommon
Elivated liver function tests
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Rare
Rash
Not known
Pruritus
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Malaise
Uncommon
Accidental fall
Investigations
Common
Weight loss
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s
disease treated with rivastigmine.
Table 2
Metabolism and nutritional
disorders
Common
Anorexia
Common
Dehydration
Psychiatric disorders
Common
Insomnia
Common
Anxiety
30
Common
Restlessness
Nervous system disorders
Very common
Tremor
Common
Dizziness
Common
Somnolence
Common
Headache
Common
Worsening of Parkinson’s disease
Common
Bradykinesia
Common
Dyskinesia
Uncommon
Dystonia
Cardiac disorders
Common
Bradycardia
Uncommon
Atrial fibrillation
Uncommon
Atrioventricular block
Gastrointestinal disorders
Very common
Nausea
Very common
Vomiting
Common
Diarrhoea
Common
Abdominal pain and dyspesia
Common
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Muscoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and
administration site conditions
Common
Fatigue and asthenia
Common
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted
with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined
adverse events that may reflect worsening of parkinsonian symptoms.
31
Table 3
Pre-defined adverse events that may reflect
worsening of parkinsonian symptoms in
patients with dementia associated with
Parkinson's disease
Rivastigmine
Placebo
n (%)
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 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.
32
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.
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.
33
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
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
Rivastigmine
ADAS-Cog
Placebo
ADCS-CGIC
Rivastigmine
ADCS-CGIC
Placebo
ITT + RDO population
(n=329)
(n=161)
(n=329)
(n=165)
Mean baseline ± SD
23.8±10.2
24.3±10.5
n/a
n/a
Mean change at 24 weeks
± SD
2.1±8.2
-0.7±7.5
3.8±1.4
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
24.0±10.3
24.5±10.6
n/a
n/a
Mean change at 24 weeks
± SD
2.5±8.4
-0.8±7.5
3.7±1.4
4.3±1.5
Adjusted treatment
difference
3.54
1
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
34
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
Rivastigmine
ADAS-Cog
Placebo
ADAS-Cog
Rivastigmine
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
25.4±9.9
27.4±10.4
23.1±10.4
22.5±10.1
Mean change at 24 weeks
± SD
1.0±9.2
-2.1±8.3
2.6±7.6
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
32.6±10.4
33.7±10.3
20.6±7.9
20.7±7.9
Mean change at 24 weeks
± SD
2.6±9.4
-1.8±7.2
1.9±7.7
-0.2±7.5
Adjusted treatment
difference
4.73
1
2.14
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
0.002
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 the drug'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.
35
p-value versus placebo
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
Capsule contents
Microcrystalline cellulose
Hypromellose
Colloidal silicon dioxide
Magnesium stearate
36
Capsule shell
Red iron oxide (E172)
Yellow iron oxide (E 172)
Titanium dioxide (E171)
Gelatin
Ink used for imprinting - Black S-1-17822/S-1-17823
Shellac glaze-45%
Iron oxide black
Ammonium hydroxide
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
This medicinal product does not require any special storage instructions.
6.5
Nature and contents of container
-
HDPE tablet container with a polypropylene cap and induction seal: 250 capsules
-
28, 56 or 112 capsules in transparent PVC/Alu push through blisters
-
50 x 1 capsules in PVC/Alu push through perforated unit dose blisters
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
8.
9.
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
37
1.
FURTHER INFORMATION
What Rivastigmine Teva contains
The active substance is rivastigmine
Rivastigmine Teva 1.5 mg hard capsules contains 1.5 mg rivastigmine as rivastigmine hydrogen
tartrate
Rivastigmine Teva 3 mg hard capsules contains 3 mg rivastigmine as rivastigmine hydrogen tartrate
Rivastigmine Teva 4.5 mg hard capsules contains 4.5 mg rivastigmine as rivastigmine hydrogen
tartrate
Rivastigmine Teva 6 mg hard capsules contains 6 mg rivastigmine as rivastigmine hydrogen tartrate
The other ingredients are:
Capsule contents - microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium
stearate.
Capsule shell – titanium dioxide (E171), gelatin and ink used for imprinting Black S-1-17822/S-1-
17823 (shellac glaze-45% in ethanol containing iron oxide black, N-butyl alcohol, isopropyl alcohol,
propylene alcohol and ammonium hydroxide). In addition, Rivastigmine Teva 3 mg, 4.5 mg and 6 mg
hard capsules contain red iron oxide (E172) and yellow iron oxide (E 172).
What Rivastigmine Teva looks like and contents of the pack
Hard capsule
-
Rivastigmine Teva 1.5 mg hard capsules: White cap imprinted with “R” & white body
imprinted with “1.5”
-
Rivastigmine Teva 3 mg hard capsules: Flesh colour cap imprinted with “R” & flesh colour
body imprinted with “3”
-
Rivastigmine Teva 4.5 mg hard capsules: Orange colour cap imprinted with “R” & orange
colour body imprinted with “4.5”
-
Rivastigmine Teva 6 mg hard capsules: Orange cap imprinted with “R” & flesh colour body
imprinted with “6”
Rivastigmine Teva hard capsules are available in blister packs of 28, 56 and 112 capsules, perforated
blisters containing 50 x 1 capsules, and bottles containing 250 capsules.
Marketing Authorisation Holder
Teva Pharma B.V.
Computerweg 10, 3542 DR Utrecht
The Netherlands
Manufacturer
TEVA Pharmaceutical Works Private Limited Company
Pallagi út 13,
4042 Debrecen,
Hungary
Or:
TEVA Pharmaceutical Works Private Limited Company
H-2100 Gödöllő,
Táncsics Mihály út 82
Hungary
Or:
81
TEVA UK Ltd
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex,
BN22 9AG
United Kingdom
Or:
Pharmachemie B.V.
Swensweg 5,
Postbus 552,
2003 RN Haarlem
The Netherlands
Or:
TEVA Santé Sa,
Rue Bellocier, 89107,
Sens,
France
Or
IVAX Pharmaceuticals s.r.o.
Ostravska 29, c.p. 305
747 70 Opava-Komarov
Czech Republic
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Teva Pharma Belgium N.V./S.A.
Tel/Tél: +32 3 820 73 73
Luxembourg/Luxemburg
Teva Pharma Belgium S.A.
Tél/Tel: +32 3 820 73 73
България
Тева Фармасютикълс България ЕООД
Teл: +359 2 489 95 82
Magyarország
Teva Magyarország Zrt
Tel.: +36 1 288 64 00
Česká republika
Teva Pharmaceuticals CR, s.r.o.
Tel: +420 251 007 111
Malta
Teva Ελλάς Α.Ε.
Τel: +30 210 72 79 099
Danmark
Teva Denmark A/S
Tlf: +45 44 98 55 11
Nederland
Teva Nederland B.V.
Tel: +31 (0) 800 0228400
Deutschland
Teva Generics GmbH
Tel: (49) 351 834 0
Norge
Teva Sweden AB
Tlf: (46) 42 12 11 00
Eesti
Teva Eesti esindus UAB Sicor Biotech Eesti
filiaal
Tel: +372 611 2409
Österreich
Teva Generics GmbH
Tel: (49) 351 834 0
Ελλάδα
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Polska
Teva Pharmaceuticals Polska Sp. z o.o.
Tel.: +(48) 22 345 93 00
82
España
Teva Genéricos Española, S.L.U
Tél: +(34) 91 387 32 80
Portugal
Teva Pharma - Produtos Farmacêuticos Lda
Tel: (351) 214 235 910
France
Teva Santé
Tél: +(33) 1 55 91 7800
România
Teva Pharmaceuticals S.R.L
Tel: +4021 230 65 24
Ireland
Teva Pharmaceuticals Ireland
Tel: +353 (0)42 9395 892
Slovenija
Pliva Ljubljana d.o.o.
Tel: +386 1 58 90 390
Ísland
Teva UK Limited
Sími: +(44) 1323 501 111.
Slovenská republika
Teva Pharmaceuticals Slovakia s.r.o.
Tel: +(421) 2 5726 7911
Italia
Teva Italia S.r.l.
Tel: +(39) 0289179805
Suomi/Finland
Teva Sweden AB
Puh/Tel: +(46) 42 12 11 00
Κύπρος
Teva Ελλάς Α.Ε.
Τηλ: +30 210 72 79 099
Sverige
Teva Sweden AB
Tel: +(46) 42 12 11 00
Latvija
UAB Sicor Biotech filiāle Latvijā
Tel: +371 67 784 980
United Kingdom
Teva UK Limited
Tel: +(44) 1323 501 111
Lietuva
UAB “Sicor Biotech”
Tel: +370 5 266 02 03
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
83
Source: European Medicines Agency
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