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Rivastigmine Hexal


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Summary for the public


What is Rivastigmine Hexal?

Rivastigmine Hexal is a medicine containing the active substance rivastigmine. It is available as capsules (yellow: 1.5 mg; orange: 3 mg; red: 4.5 mg; red and orange: 6 mg) and as an oral solution (2 mg/ml).

This medicine is the same as the capsules and oral solution of Exelon, a medicine that is already authorised in the European Union (EU). The company that makes Exelon has agreed that its scientific data can be used for Rivastigmine Hexal (‘informed consent’).


What is Rivastigmine Hexal used for?

Rivastigmine Hexal is used for the treatment of patients with mild to moderately severe Alzheimer’s dementia, a progressive brain disorder that gradually affects memory, intellectual ability and behaviour. Rivastigmine Hexal is also used to treat mild to moderately severe dementia in patients with Parkinson’s disease.

The medicine can only be obtained with a prescription.


How is Rivastigmine Hexal used?

Treatment with Rivastigmine Hexal should be initiated and supervised by a doctor who has experience in the diagnosis and treatment of Alzheimer’s disease or dementia in patients with Parkinson’s disease. Treatment should only be started if a caregiver is available who will regularly monitor the use of Rivastigmine Hexal by the patient. Treatment should continue as long as the medicine has a benefit, but the dose can be reduced or treatment interrupted if the patient has side effects.

Rivastigmine Hexal should be given twice a day, with morning and evening meals. The capsules should be swallowed whole. The starting dose is 1.5 mg twice a day. In patients who tolerate this dose, it can be increased in 1.5-mg steps no more frequently than every two weeks, to a regular dose of 3 to 6 mg twice a day. The highest tolerated dose should be used to get the maximum benefit, but the dose should not exceed 6 mg twice a day.


How does Rivastigmine Hexal work?

The active substance in Rivastigmine Hexal, rivastigmine, is an antidementia medicine. In patients with Alzheimer’s dementia or dementia due to Parkinson’s disease, certain nerve cells die in the brain, resulting in low levels of the neurotransmitter acetylcholine (a chemical that allows nerve cells to communicate with each other). Rivastigmine works by blocking the enzymes that break down acetylcholine: acetylcholinesterase and butyrylcholinesterase. By blocking these enzymes, Rivastigmine Hexal allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of Alzheimer’s dementia and dementia due to Parkinson’s disease.


How has Rivastigmine Hexal been studied?

Rivastigmine Hexal has been studied in three main studies involving 2,126 patients with mild to moderately severe Alzheimer’s disease. Rivastigmine Hexal was also studied in 541 patients with dementia due to Parkinson’s disease. All of the studies lasted six months and compared the effects of Rivastigmine Hexal with those of placebo (a dummy treatment). The main measures of effectiveness were the change in symptoms in two main areas: cognitive (the ability to think, learn and remember) and global (a combination of several areas including general function, cognitive symptoms, behaviour and the ability to carry out everyday activities).

An additional study in 27 patients was used to show that Rivastigmine Hexal capsules and oral solution produced similar levels of the active substance in the blood.


What is the risk associated with Rivastigmine Hexal?

The types of side effects seen with Rivastigmine Hexal depend on the type of dementia it is being used to treat. Overall, the most common side effects (seen in more than 1 patient in 10) include nausea (feeling sick) and vomiting, particularly during the phase when the dose of Rivastigmine Hexal is being increased. For the full list of all side effects reported with Rivastigmine Hexal, see the Package Leaflet.

Rivastigmine Hexal should not be used in people who may be hypersensitive (allergic) to rivastigmine, other carbamate derivatives or any of the other ingredients. It should not be used in patients with severe liver problems.


Why has Rivastigmine Hexal been approved?

The Committee for Medicinal Products for Human Use (CHMP) concluded that Rivastigmine Hexal has a modest effectiveness in treating the symptoms of Alzheimer’s dementia, although this does reflect an important benefit in some patients. The Committee initially concluded that for the treatment of dementia due to Parkinson’s disease, Rivastigmine Hexal’s benefits did not outweigh its risks. However, following a re-examination of this opinion, the Committee concluded that the medicine’s modest effectiveness could also be of benefit to some patients.

Therefore, the Committee decided that Rivastigmine Hexal’s benefits are greater than its risks for the treatment of mild to moderately severe Alzheimer’s dementia and mild to moderately severe dementia in patients with idiopathic Parkinson’s disease. The Committee recommended that Rivastigmine Hexal be given marketing authorisation.


Other information about Rivastigmine Hexal:

The European Commission granted a marketing authorisation valid throughout the EU to Hexal AG for Rivastigmine Hexal on 11 December 2009. The marketing authorisation is valid for five years, after which it can be renewed.

Authorisation details
Name: Rivastigmine Hexal
EMEA Product number: EMEA/H/C/001182
Active substance: rivastigmine
INN or common name: rivastigmine
Therapeutic area: DementiaParkinson DiseaseAlzheimer Disease
ATC Code: N06DA03
Generic: A generic medicine is a medicine which is similar to a medicine that has already been authorised (the 'reference medicine'). A generic medicine contains the same quantity of active substance(s) as the reference medicine. Generic and reference medicines are used at the same dose to treat the same disease, and they are equally safe and effective.
Marketing Authorisation Holder: Hexal AG
Revision: 1
Date of issue of Market Authorisation valid throughout the European Union: 11/12/2009
Contact address:
Hexal AG
Industriestrasse 25
D-83607 Holzkirchen
Germany




Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT
Rivastigmine HEXAL 1.5 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule
Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint
“RIV 1.5 mg” on the body.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in the diagnosis and
treatment of Alzheimer’s dementia 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.
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.
4.3 Contraindications
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.
4.4 Special warnings and precautions for use
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
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
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.
4.8 Undesirable effects
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
Gastrointestinal disorders
Very common
Very common
Very common
Nausea
Vomiting
Diarrhoea
5
 
Common
Rare
Very rare
Very rare
Not known
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
The following additional adverse reactions have been observed with rivastigmine transdermal patches:
anxiety, delirium, pyrexia (common).
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
Arial fibrillation
Atrioventricular block
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
6
 
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 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
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
4.9 Overdose
Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient
fully recovered within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse
reactions should be given as necessary.
7
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote
is not recommended.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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.
8
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
Mean baseline ± SD
Mean change at
24 weeks ± SD
(n=329)
23.8 ± 10.2
2.1 ± 8.2
(n=161)
24.3 ± 10.5
-0.7 ± 7.5
(n=329)
n/a
3.8 ± 1.4
(n=165)
n/a
4.3 ± 1.5
Adjusted treatment
difference
p-value versus placebo
2.88 1
<0.001 1
n/a
0.007 2
ITT - LOCF population
Mean baseline ± SD
Mean change at
24 weeks ± SD
(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).
9
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 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
10
Adjusted treatment
difference
p-value versus placebo
 
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. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
11
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or 8
blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
HEXAL AG
Industriestraße 25
83607 Holzkirchen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/09/589/001
EU/1/09/589/002
EU/1/09/589/003
EU/1/09/589/004
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/12/2009
10. DATE OF REVISION OF THE TEXT
….
Detailed information is available on the European Medicines Agency (EMA) website:
http://www.ema.europa.eu
12
1. NAME OF THE MEDICINAL PRODUCT
Rivastigmine HEXAL 3 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule
Off-white to slightly yellow powder in a capsule with orange cap and orange body, with red imprint
“RIV 3 mg” on the body.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in the diagnosis and
treatment of Alzheimer’s dementia 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
13
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.
4.3 Contraindications
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.
4.4 Special warnings and precautions for use
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
14
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
15
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.
4.8 Undesirable effects
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
Gastrointestinal disorders
Very common
Very common
Very common
Common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
16
 
Rare
Very rare
Very rare
Not known
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
The following additional adverse reactions have been observed with rivastigmine transdermal patches:
anxiety, delirium, pyrexia (common).
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
Arial fibrillation
Atrioventricular block
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
17
 
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 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
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
4.9 Overdose
Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient
fully recovered within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse
reactions should be given as necessary.
18
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote
is not recommended.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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
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
Mean baseline ± SD
Mean change at
24 weeks ± SD
(n=329)
23.8 ± 10.2
2.1 ± 8.2
(n=161)
24.3 ± 10.5
-0.7 ± 7.5
(n=329)
n/a
3.8 ± 1.4
(n=165)
n/a
4.3 ± 1.5
Adjusted treatment
difference
p-value versus placebo
2.88 1
<0.001 1
n/a
0.007 2
ITT - LOCF population
Mean baseline ± SD
Mean change at
24 weeks ± SD
(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).
20
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 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
21
Adjusted treatment
difference
p-value versus placebo
 
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. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
22
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or 8
blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
HEXAL AG
Industriestraße 25
83607 Holzkirchen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/09/589/005
EU/1/09/589/006
EU/1/09/589/007
EU/1/09/589/008
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/12/2009
10. DATE OF REVISION OF THE TEXT
….
Detailed information is available on the European Medicines Agency (EMA) website:
23
1. NAME OF THE MEDICINAL PRODUCT
Rivastigmine HEXAL 4.5 mg hard capsules
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg.
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Hard capsule
Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint “RIV
4.5 mg” on the body.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
Treatment should be initiated and supervised by a physician experienced in the diagnosis and
treatment of Alzheimer’s dementia 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
24
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.
4.3 Contraindications
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.
4.4 Special warnings and precautions for use
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
25
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.
4.5 Interaction with other medicinal products and other forms of interaction
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.
4.6 Fertility, pregnancy and lactation
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.
4.7 Effects on ability to drive and use machines
26
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.
4.8 Undesirable effects
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
Gastrointestinal disorders
Very common
Very common
Very common
Common
Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
27
 
Rare
Very rare
Very rare
Not known
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
The following additional adverse reactions have been observed with rivastigmine transdermal patches:
anxiety, delirium, pyrexia (common).
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
Arial fibrillation
Atrioventricular block
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
28
 
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 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
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
4.9 Overdose
Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient
fully recovered within 24 hours.
Treatment
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse
reactions should be given as necessary.
29
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote
is not recommended.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: 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.
30
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
Mean baseline ± SD
Mean change at
24 weeks ± SD
(n=329)
23.8 ± 10.2
2.1 ± 8.2
(n=161)
24.3 ± 10.5
-0.7 ± 7.5
(n=329)
n/a
3.8 ± 1.4
(n=165)
n/a
4.3 ± 1.5
Adjusted treatment
difference
p-value versus placebo
2.88 1
<0.001 1
n/a
0.007 2
ITT - LOCF population
Mean baseline ± SD
Mean change at
24 weeks ± SD
(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).
31
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 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
32
Adjusted treatment
difference
p-value versus placebo
 
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. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Gelatin
Magnesium stearate
Hypromellose
Microcrystalline cellulose
Silica, colloidal anhydrous
Yellow iron oxide (E172)
Red iron oxide (E172)
Titanium dioxide (E171)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
5 years
6.4 Special precautions for storage
Do not store above 30°C.
33
6.5 Nature and contents of container
-
Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or 8
blisters.
-
HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
HEXAL AG
Industriestraße 25
83607 Holzkirchen
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/09/589/009
EU/1/09/589/010
EU/1/09/589/011
EU/1/09/589/012
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/12/2009
10. DATE OF REVISION OF THE TEXT
….
Detailed information is available on the European Medicines Agency (EMA) website:
34
6. FURTHER INFORMATION
What Rivastigmine HEXAL contains
- The active substance is rivastigmine hydrogen tartrate. Each ml contains rivastigmine hydrogen
tartrate corresponding to rivastigmine base 2.0 mg.
- The other ingredients are sodium benzoate, citric acid, sodium citrate, quinoline yellow WS dye
(E104) and purified water.
What Rivastigmine HEXAL looks like and contents of the pack
Rivastigmine HEXAL oral solution is supplied as 50 ml or 120 ml of a clear, yellow solution
(2.0 mg/ml base) in an amber glass bottle with a child-resistant cap, foam liner, dip tube and self
aligning plug. The oral solution is packaged with an oral dosing syringe in a plastic tube container.
Marketing Authorisation Holder
HEXAL AG
Industriestraße 25
D-83607 Holzkirchen
Germany
Manufacturer
Novartis Pharma S.A.S.
26, rue de la Chapelle
F-68333 Huningue
France
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Sandoz N.V.
Telecom Gardens
Medialaan 40
B-1800 Vilvoorde
Tel: +32 (0)2 722 97 98
Luxembourg/Luxemburg
HEXAL AG
Industriestraße 25
D-83607 Holzkirchen
Tél/Tel: + 49 8024 908 0
E-mail: service@hexal.com
България
Representative office Sandoz d.d.
Magyarország
Sandoz Hungária Kft.
95
Business Park Sofia, buil. 8B, fl. 6
BG-1766 Sofia
Tel.: + 359 2 970 47 48
Tímár u. 20.
H-1034 Budapest
Phone: +36 1 430 2890
Česká republika
Sandoz s.r.o.
Jeseniova 30
CZ-13000 Praha 3
E-mail: office.cz@sandoz.com
Tel: +420 221 421 612
Malta
V.J. Salomone Pharma Ltd.
79, Simpson Street
MT-Marsa HMR14
Phone: +356 21 220 174
Danmark
Sandoz A/S
Edvard Thomsens Vej 14
DK-2300 København S
E-mail: info.sandoz-dk@sandoz.com
Nederland
Sandoz B.V.
Veluwezoom 22
NL-1327 AH Almere
Tel: +31 36 5241600
Deutschland
HEXAL AG
Industriestraße 25
D-83607 Holzkirchen
Tel: + 49 8024 908 0
E-mail: service@hexal.com
Norge
Sandoz A/S
Edvard Thomsens Vej 14
DK-2300 København S
E-mail: info.sandoz-dk@sandoz.com
Eesti
Sandoz d.d. Eesti filiaal,
Pärnu mnt 105,
EE-11312 Tallinn,
Tel: +372 6652401
Österreich
HEXAL Pharma GmbH
Carlbergergasse 44
A-1235 Wien
Tel: + 43 (0)1 486 96 22
Ελλάδα
Sambrook Faρµaκeυtική Α.Ε.
Κaζaνtζάκη 4 & Αγ. Πaνteλeήµονος
GR-135 61 Αγ. Ανάργυροι
tηλ : +30 -210 -85 40053
e-µέϊλ: ysotirakou@sambrook.gr
Polska
Lek Polska Sp.z o.o.
ul. Domaniewska 50 C
PL - 02-672 Warszawa
Phone: +48 22 549 15 00
España
Bexal Farmaceutica S.A.
Av/Osa Mayor no 4, Area B
E-28023 Aravaca / Madrid
E-mail: sandoz.responde@sandoz.com
Portugal
Sandoz Farmacêutica Lda.
Alameda da Beloura
Edifício 1, 2º andar - Escritório 15
2710-693 Sintra
Phone: +351 21 0008782
France
Sandoz SAS
49, avenue Georges Pompidou
F-92593 Levallois-Perret Cedex
Tel: +33 1 4964 4801
România
Sandoz Pharma Services S.R.L.
Victoria Business Park
RO-Soseaua Bucuresti-Ploiesti 73-81
Corp 2, etaj 2, Sector 1
Phone: +40 21 4075184
Ireland
Rowex Ltd.
Newtown
IE - Bantry Co. Cork
Slovenija
Lek Pharmaceuticals d.d.
Verovśkova 57
SI-1526 Ljubljana
96
Tel: + 353 27 50077
Tel: +386 1 5802111
Ísland
Sandoz A/S
Edvard Thomsens Vej 14
DK-2300 København S
E-mail: info.sandoz-dk@sandoz.com
Slovenská republika
Sandoz d.d. - organizačná zložka
Galvaniho 15/C
SK-821 04 Bratislava
Tel: +421 2 48 200 601
Italia
Hexal S.p.A. c/o Sandoz S.p.A.
Largo Umberto Boccioni 1
I-21040 Origgio / VA
Tel: + 39-02-96 541
Suomi/Finland
Sandoz A/S
Edvard Thomsens Vej 14
DK-2300 København S
E-mail: info.sandoz-dk@sandoz.com
Κύπρος
Π.T.Χatζηγeωργίου etaιρeίa Λtd
Gιλdίζ 31-3042 Λeµesός
Τηλέfωνο: 00357 25372425
Faξ: 00357 25376400
e-µέϊλ: hapanicos@cytanet.com.cy
Sverige
Sandoz A/S
Edvard Thomsens Vej 14
DK-2300 København S
E-mail: info.sandoz-dk@sandoz.com
Latvija
Sandoz d.d. Representative Office in Latvia
Meza Str. 4
LV-1048, Riga
Phone: +371 67892007
United Kingdom
Sandoz Ltd
37 Woolmer Way
Bordon GU35 9QE – UK
Tel: +44 (0) 1420 478301
Lietuva
Sandoz Pharmaceuticals d.d.,
Branch Office Lithuania
Seimyniskiu Str. 3A
LT-09312 Vilnius
Phone: +370 5 2636038
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency (EMA) web
97
Instructions for Use: Rivastigmine HEXAL oral solution
1.
Remove oral dosing syringe from its protective case. Push down and turn child resistant
closure to open bottle.
2.
Insert nozzle of syringe into opening of white stopper.
98
3.
Withdraw prescribed amount of Rivastigmine HEXAL oral solution from bottle.
4.
Before removing syringe containing prescribed dose from bottle, expel any large bubbles by
depressing and withdrawing plunger a few times. The presence of a few tiny bubbles is of no
importance and will not affect the dose in any way.
99
5.
Swallow Rivastigmine HEXAL oral solution directly from the syringe or first mix in a small
glass with water. Stir and drink the entire mixture.
6.
After use, wipe outside of syringe with a clean tissue and replace it in its protective case.
Close bottle using child resistant closure.
100


Source: European Medicines Agency



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