ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Nimvastid 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 to almost white powder in a capsule with yellow cap and yellow 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.
Maintenance dose
2
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.
If treatment is interrupted for more than several days, it should be reinitiated 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
3
Re-initiation of therapy
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 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
Common
Uncommon
Uncommon
Very rare
Agitation
Confusion
Insomnia
Depression
Hallucinations
Nervous system disorders
Very common
Common
Common
Common
Uncommon
Rare
Very rare
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Cardiac disorders
Rare
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular
block, atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
5
Gastrointestinal disorders
Very common
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
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).
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue
disorders
Common
Rare
Not known
Sweating increased
Rash
Pruritus
General disorders and administration
site conditions
Common
Common
Uncommon
Fatigue and asthenia
Malaise
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
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Common
Common
Insomnia
Anxiety
Restlessness
Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Uncommon
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Cardiac disorders
Common
Uncommon
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
6
Gastrointestinal disorders
Very common
Very common
Common
Common
Common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Common
Fatigue and asthenia
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinicalstudy 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
n (%)
Placebo
n (%)
Total patients studied
Total patients with pre-defined AE(s)
362 (100)
99 (27.3)
179 (100)
28 (15.6)
Tremor
Fall
Parkinson's disease (worsening)
Salivary hypersecretion
Dyskinesia
Parkinsonism
Hypokinesia
Movement disorder
Bradykinesia
Dystonia
Gait abnormality
Muscle rigidity
Balance disorder
Musculoskeletal stiffness
Rigors
Motor dysfunction
37 (10.2)
21 (5.8)
12 (3.3)
5 (1.4)
5 (1.4)
8 (2.2)
1 (0.3)
1 (0.3)
9 (2.5)
3 (0.8)
5 (1.4)
1 (0.3)
3 (0.8)
3 (0.8)
1 (0.3)
1 (0.3)
7 (3.9)
11 (6.1)
2 (1.1)
0
1 (0.6)
1 (0.6)
0
0
3 (1.7)
1 (0.6)
0
0
2 (1.1)
0
0
0
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.
7
Symptoms
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.
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
8
Treatment
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
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
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
p-value versus placebo
ITT - LOCF population
Mean baseline ± SD
Mean change at 24 weeks
± SD
2.88
1
<0.
0
01
1
n/a
0.0
0
7
2
(n=287)
24.0 ± 10.3
2.5 ± 8.4
(n=154)
24.5 ± 10.6
-0.8 ± 7.5
(n=289)
n/a
3.7 ± 1.4
(n=158)
n/a
4.3 ± 1.5
n/a
<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
<0.001
1
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
9
Clinical studies in dementia associated with Parkinson’s disease
Adjusted treatment difference
p-value versus placebo
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
Mean baseline ± SD
Mean change at 24 weeks
± SD
(n=107)
25.4 ± 9.9
1.0 ± 9.2
(n=60)
27.4 ± 10.4
-2.1 ± 8.3
(n=220)
23.1 ± 10.4
2.6 ± 7.6
(n=101)
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment difference
p-value versus placebo
4.27
1
0.002
1
2.09
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks ±
SD
(n=87)
32.6 ± 10.4
2.6 ± 9.4
(n=44)
33.7 ± 10.3
-1.8 ± 7.2
(n=237)
20.6 ± 7.9
1.9 ± 7.7
(n=115)
20.7 ± 7.9
-0.2 ± 7.5
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
4.73
1
0.002
1
5.2 Pharmacokinetic properties
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in
approximately 1 hour. As a consequence of the rivastigmin’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 (tmax) 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.
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
10
Adjusted treatment difference
p-value versus placebo
Absorption
Metabolism
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route
of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and
essentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the
faeces. There is no accumulation of rivastigmine or the decarbamylated metabolite in patients with
Alzheimer’s disease.
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.
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 content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate
Capsule shell
Titanium dioxide (E171),
Yellow iron oxide (E172),
Gelatine
6.2 Incompatibilities
11
Elderly subjects
Subjects with renal impairment
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
Blister pack (PVC/PVDC/Al-foil): 14, 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
14 hard capsules: EU/1/09/525/001
28 hard capsules: EU/1/09/525/002
30 hard capsules: EU/1/09/525/003
56 hard capsules: EU/1/09/525/004
60 hard capsules: EU/1/09/525/005
112 hard capsules: EU/1/09/525/006
200 hard capsules: EU/1/09/525/047
250 hard capsules: EU/1/09/525/007
9.
11/5/2009
Detailed information on this medicine is available on the European Medicines Agency
12
1.
Nimvastid 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.
White to almost white powder in a capsule with orange cap and orange 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.
1.5 mg twice a day.
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.
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.
13
Initial dose
Dose titration
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.
If treatment is interrupted for more than several days, it should be reinitiated 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.
14
Re-initiation of therapy
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.
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
15
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
Common
Uncommon
Uncommon
Very rare
Agitation
Confusion
Insomnia
Depression
Hallucinations
Nervous system disorders
Very common
Common
Common
Common
Uncommon
Rare
Very rare
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Cardiac disorders
Rare
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular
block, atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
16
Gastrointestinal disorders
Very common
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
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).
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue
disorders
Common
Rare
Not known
Sweating increased
Rash
Pruritus
General disorders and administration
site conditions
Common
Common
Uncommon
Fatigue and asthenia
Malaise
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
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Common
Common
Insomnia
Anxiety
Restlessness
Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Uncommon
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Cardiac disorders
Common
Uncommon
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
17
Gastrointestinal disorders
Very common
Very common
Common
Common
Common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Common
Fatigue and asthenia
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinicalstudy 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
n (%)
Placebo
n (%)
Total patients studied
Total patients with pre-defined AE(s)
362 (100)
99 (27.3)
179 (100)
28 (15.6)
Tremor
Fall
Parkinson's disease (worsening)
Salivary hypersecretion
Dyskinesia
Parkinsonism
Hypokinesia
Movement disorder
Bradykinesia
Dystonia
Gait abnormality
Muscle rigidity
Balance disorder
Musculoskeletal stiffness
Rigors
Motor dysfunction
37 (10.2)
21 (5.8)
12 (3.3)
5 (1.4)
5 (1.4)
8 (2.2)
1 (0.3)
1 (0.3)
9 (2.5)
3 (0.8)
5 (1.4)
1 (0.3)
3 (0.8)
3 (0.8)
1 (0.3)
1 (0.3)
7 (3.9)
11 (6.1)
2 (1.1)
0
1 (0.6)
1 (0.6)
0
0
3 (1.7)
1 (0.6)
0
0
2 (1.1)
0
0
0
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.
18
Symptoms
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.
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.
19
Treatment
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).
20
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
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
p-value versus placebo
ITT - LOCF population
Mean baseline ± SD
Mean change at 24 weeks
± SD
2.88
1
<0.
0
01
1
n/a
0.0
0
7
2
(n=287)
24.0 ± 10.3
2.5 ± 8.4
(n=154)
24.5 ± 10.6
-0.8 ± 7.5
(n=289)
n/a
3.7 ± 1.4
(n=158)
n/a
4.3 ± 1.5
n/a
<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
<0.001
1
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).
21
Adjusted treatment difference
p-value versus placebo
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
Mean baseline ± SD
Mean change at 24 weeks
± SD
(n=107)
25.4 ± 9.9
1.0 ± 9.2
(n=60)
27.4 ± 10.4
-2.1 ± 8.3
(n=220)
23.1 ± 10.4
2.6 ± 7.6
(n=101)
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment difference
p-value versus placebo
4.27
1
0.002
1
2.09
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks ±
SD
(n=87)
32.6 ± 10.4
2.6 ± 9.4
(n=44)
33.7 ± 10.3
-1.8 ± 7.2
(n=237)
20.6 ± 7.9
1.9 ± 7.7
(n=115)
20.7 ± 7.9
-0.2 ± 7.5
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
4.73
1
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 rivastigmin’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 (tmax) by 90 min and lowers C
max
and increases AUC by approximately 30%.
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.
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route
of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and
22
Adjusted treatment difference
p-value versus placebo
Distribution
Excretion
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.
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 content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate
Capsule shell
Titanium dioxide (E171),
Yellow iron oxide (E172),
Red iron oxide (E172)
Gelatine
6.2 Incompatibilities
Not applicable.
23
Subjects with hepatic impairment
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
Blister pack (PVC/PVDC/Al-foil): 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
28 hard capsules: EU/1/09/525/008
30 hard capsules: EU/1/09/525/009
56 hard capsules: EU/1/09/525/010
60 hard capsules: EU/1/09/525/011
112 hard capsules: EU/1/09/525/012
200 hard capsules: EU/1/09/525/048
250 hard capsules: EU/1/09/525/013
9.
11/5/2009
Detailed information on this medicine is available on the European Medicines Agency
24
1.
Nimvastid 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.
White to almost white powder in a capsule with brownish red cap and brownish red 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.
Maintenance dose
25
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.
If treatment is interrupted for more than several days, it should be reinitiated 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
26
Re-initiation of therapy
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.
27
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
Common
Uncommon
Uncommon
Very rare
Agitation
Confusion
Insomnia
Depression
Hallucinations
Nervous system disorders
Very common
Common
Common
Common
Uncommon
Rare
Very rare
Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson’s disease)
Cardiac disorders
Rare
Very rare
Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular
block, atrial fibrillation and tachycardia)
Vascular disorders
Very rare
Hypertension
28
Gastrointestinal disorders
Very common
Very common
Very common
Common
Rare
Very rare
Very rare
Not known
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).
Hepatobiliary disorders
Uncommon
Elevated liver function tests
Skin and subcutaneous tissue
disorders
Common
Rare
Not known
Sweating increased
Rash
Pruritus
General disorders and administration
site conditions
Common
Common
Uncommon
Fatigue and asthenia
Malaise
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
Common
Anorexia
Dehydration
Psychiatric disorders
Common
Common
Common
Insomnia
Anxiety
Restlessness
Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Uncommon
Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson’s disease
Bradykinesia
Dyskinesia
Dystonia
Cardiac disorders
Common
Uncommon
Uncommon
Bradycardia
Atrial Fibrillation
Atrioventricular block
29
Gastrointestinal disorders
Very common
Very common
Common
Common
Common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion
Skin and subcutaneous tissue
disorders
Common
Sweating increased
Musculoskeletal and connective tissue
disorders
Common
Muscle rigidity
General disorders and administration
site conditions
Common
Common
Fatigue and asthenia
Gait abnormality
Table 3 lists the number and percentage of patients from the specific 24-week clinicalstudy 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
n (%)
Placebo
n (%)
Total patients studied
Total patients with pre-defined AE(s)
362 (100)
99 (27.3)
179 (100)
28 (15.6)
Tremor
Fall
Parkinson's disease (worsening)
Salivary hypersecretion
Dyskinesia
Parkinsonism
Hypokinesia
Movement disorder
Bradykinesia
Dystonia
Gait abnormality
Muscle rigidity
Balance disorder
Musculoskeletal stiffness
Rigors
Motor dysfunction
37 (10.2)
21 (5.8)
12 (3.3)
5 (1.4)
5 (1.4)
8 (2.2)
1 (0.3)
1 (0.3)
9 (2.5)
3 (0.8)
5 (1.4)
1 (0.3)
3 (0.8)
3 (0.8)
1 (0.3)
1 (0.3)
7 (3.9)
11 (6.1)
2 (1.1)
0
1 (0.6)
1 (0.6)
0
0
3 (1.7)
1 (0.6)
0
0
2 (1.1)
0
0
0
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.
30
Symptoms
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.
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.
31
Treatment
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).
32
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
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
p-value versus placebo
ITT – LOCF population
Mean baseline ± SD
Mean change at 24 weeks
± SD
2.88
1
<0.
0
01
1
n/a
0.0
0
7
2
(n=287)
24.0 ± 10.3
2.5 ± 8.4
(n=154)
24.5 ± 10.6
-0.8 ± 7.5
(n=289)
n/a
3.7 ± 1.4
(n=158)
n/a
4.3 ± 1.5
n/a
<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
<0.001
1
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).
33
Adjusted treatment difference
p-value versus placebo
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
Mean baseline ± SD
Mean change at 24 weeks
± SD
(n=107)
25.4 ± 9.9
1.0 ± 9.2
(n=60)
27.4 ± 10.4
-2.1 ± 8.3
(n=220)
23.1 ± 10.4
2.6 ± 7.6
(n=101)
22.5 ± 10.1
0.1 ± 6.9
Adjusted treatment difference
p-value versus placebo
4.27
1
0.002
1
2.09
1
0.015
1
Patients with moderate
dementia (MMSE 10-17)
Patients with mild dementia
(MMSE 18-24)
ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks ±
SD
(n=87)
32.6 ± 10.4
2.6 ± 9.4
(n=44)
33.7 ± 10.3
-1.8 ± 7.2
(n=237)
20.6 ± 7.9
1.9 ± 7.7
(n=115)
20.7 ± 7.9
-0.2 ± 7.5
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
4.73
1
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 rivastigmin’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 (tmax) by 90 min and lowers C
max
and increases AUC by approximately 30%.
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.
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route
of elimination. Following administration of 14C-rivastigmine, renal elimination was rapid and
34
Adjusted treatment difference
p-value versus placebo
Distribution
Excretion
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.
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 content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate
Capsule shell
Titanium dioxide (E171),
Yellow iron oxide (E172),
Red iron oxide (E172)
Gelatine
6.2 Incompatibilities
Not applicable.
35
Subjects with hepatic impairment
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
Blister pack (PVC/PVDC/Al-foil): 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements
7.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
8.
28 hard capsules: EU/1/09/525/014
30 hard capsules: EU/1/09/525/015
56 hard capsules: EU/1/09/525/016
60 hard capsules: EU/1/09/525/017
112 hard capsules: EU/1/09/525/018
200 hard capsules: EU/1/09/525/049
250 hard capsules: EU/1/09/525/019
9.
11/5/2009
Detailed information on this medicine is available on the European Medicines Agency
36
1.
FURTHER INFORMATION
What Nimvastid contains
-
The active substance is rivastigmine hydrogen tartrate.
Each Nimvastid 1.5 mg orodispersible tablet contains 1.5 mg of rivastigmine as rivastigmine
hydrogen tartrate.
Each Nimvastid 3 mg orodispersible tablet contains 3 mg of rivastigmine as rivastigmine
hydrogen tartrate.
Each Nimvastid 4.5 mg orodispersible tablet contains 4.5 mg of rivastigmine as rivastigmine
hydrogen tartrate.
Each Nimvastid 6 mg orodispersible tablet contains 6 mg of rivastigmine as rivastigmine
hydrogen tartrate.
-
The other ingredients are mannitol, microcrystalline cellulose, hydroxypropylcellulose,
spearmint flavour (peppermint oil, maize maltodextrin), peppermint flavour (maltodextrine,
gum arabic, sorbitol E420, corn mint oil, L-menthol), crospovidone, calcium silicate,
magnesium stearate.
What Nimvastid looks like and contents of the pack
Orodispersible tablets are round and white tablets.
14 x 1 (only for 1.5 mg), 28 x 1, 30 x 1, 56 x 1, 60 x 1 or 112 x 1 tablet in OPA/Al/PVC foil film and
PET/Al peel off foil perforated unit dose blister packs are available.
Not all pack sizes may be marketed.
135
Marketing Authorisation Holder and Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
Luxembourg/Luxemburg
KRKA, d.d., Novo mesto
Tél/Tel:
+
32 (0)3 321 63 52
България
Представителство на KRKA в България
Teл.:
+
359 (02)
962 34 50
Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.:
+
361 (0) 355 8490
Česká republika
KRKA ČR, s.r.o.
Tel:
+
420 (0) 221 115 150
Malta
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Danmark
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Nederland
KRKA, d.d., Novo mesto
Tel:
+
32 3 321 63 52 (BE)
Deutschland
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Norge
KRKA Sverige AB
Tlf:
+
46 (0)8 643 67 66 (SE)
Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel:
+
372 (0)6 597 365
Österreich
TAD Pharma GmbH
Tel:
+
49 (0) 4721 6060
Ελλάδα
KRKA, d.d., Novo mesto
Τηλ:
+
30 (0)210 9581143
Polska
KRKA Polska Sp.z.o.o
Tel.:
+
48 (0)22 573 7500
España
KRKA, d.d., Novo mesto
Tel:
+
34 (0)61 5089 809
Portugal
KRKA Farmacêutica, Unipessoal Lda.
Tel:
+
351 (0)21 46 43 650
France
KRKA, d.d., Novo mesto
Tél:
+
32 3 321 63 52 (BE)
România
KRKA, d.d., Novo mesto
Reprezentanţa pentru România
Tel:
+
402 (0)1 310 66 05
Ireland
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Slovenija
KRKA, d.d., Novo mesto
Tel:
+
386 (0) 1 47 51 100
Ísland
KRKA Sverige AB
Sími:
+
46 (0)8 643 67 66 (SE)
Slovenská republika
KRKA Slovensko, s.r.o.,
Tel:
+
421 (0) 2 571 04 501
Italia
KRKA, d.d., Novo mesto
Tel:
+
39 069448827
Suomi/Finland
KRKA Sverige AB
Puh/Tel:
+
46 (0)8 643 67 66 (SE)
136
Κύπρος
KRKA, d.d., Novo mesto
Τηλ:
+
30 (0)210 9581143 (EL)
Sverige
KRKA Sverige AB
Tel:
+
46 (0)8 643 67 66 (SE)
Latvija
KRKA, d.d., Novo mesto
Tel:
+
371 (0)733 8610
United Kingdom
KRKA Pharma Dublin, Ltd.
Tel:
+
46 8 643 67 66
Lietuva
KRKA, d.d., Novo mesto
Tel:
+
370 5 236 27 40
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency
137
Source: European Medicines Agency
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