Nimvastid

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 1.5 mg rivastigmine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

White to almost white powder in a capsule with yellow cap and yellow 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.

Posology
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



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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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid capsules may be used in this patient population 
provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).



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Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



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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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to 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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.



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Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness



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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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common

Insomnia
Anxiety
Restlessness



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Common
Common
Not known

Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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)



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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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties



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Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444

ADAS-Cog: improvement 
of at least 4 points

21*** 12 25*** 12

CIBIC-Plus: improvement 29*** 18 32*** 19
PDS: improvement of at 
least 10%

26*** 17 30*** 18

At least 4 points 10* 6 12** 6



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improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
*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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

Patients with visual 
hallucinations

Patients without visual 
hallucinations



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ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 
CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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 



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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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate

Capsule shell



14

Titanium dioxide (E171),
Yellow iron oxide (E172),
Gelatine

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 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/Alu-foil): 14, 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

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. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT



15

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



16

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 3 mg rivastigmine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

White to almost white powder in a capsule with orange cap and orange 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.

Posology
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



17

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid capsules may be used in this patient population 
provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).



18

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



19

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to 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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.



20

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness



21

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common

Insomnia
Anxiety
Restlessness



22

Common
Common
Not known

Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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)



23

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties



24

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444

ADAS-Cog: improvement 
of at least 4 points

21*** 12 25*** 12

CIBIC-Plus: improvement 29*** 18 32*** 19
PDS: improvement of at 
least 10%

26*** 17 30*** 18

At least 4 points 10* 6 12** 6



25

improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
*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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

Patients with visual 
hallucinations

Patients without visual 
hallucinations



26

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 
CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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 



27

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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate

Capsule shell



28

Titanium dioxide (E171),
Yellow iron oxide (E172),
Red iron oxide (E172)
Gelatine

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 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/Alu-foil): 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

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. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



29

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 4.5 mg rivastigmine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

White to almost white powder in a capsule with brownish red cap and brownish red 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.

Posology
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



30

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid capsules may be used in this patient population 
provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).



31

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



32

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to 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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.



33

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness



34

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common

Insomnia
Anxiety
Restlessness



35

Common
Common
Not known

Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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)



36

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties



37

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444

ADAS-Cog: improvement 
of at least 4 points

21*** 12 25*** 12

CIBIC-Plus: improvement 29*** 18 32*** 19
PDS: improvement of at 
least 10%

26*** 17 30*** 18

At least 4 points 10* 6 12** 6



38

improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
*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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

Patients with visual 
hallucinations

Patients without visual 
hallucinations



39

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 
CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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 



40

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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate

Capsule shell



41

Titanium dioxide (E171),
Yellow iron oxide (E172),
Red iron oxide (E172)
Gelatine

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 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/Alu-foil): 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

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. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



42

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 6 mg rivastigmine.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

White to almost white powder in a capsule with a brownish red cap and orange 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.

Posology
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



43

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid capsules may be used in this patient population 
provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).



44

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



45

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to 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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.



46

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness



47

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common

Insomnia
Anxiety
Restlessness



48

Common
Common
Not known

Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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)



49

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties



50

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444

ADAS-Cog: improvement 
of at least 4 points

21*** 12 25*** 12

CIBIC-Plus: improvement 29*** 18 32*** 19
PDS: improvement of at 
least 10%

26*** 17 30*** 18

At least 4 points 10* 6 12** 6



51

improvement on ADAS-
Cog with no worsening on
CIBIC-Plus and PDS
*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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

Patients with visual 
hallucinations

Patients without visual 
hallucinations



52

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 
CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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 



53

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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule content
Microcrystalline cellulose
Hypromellose
Silica, colloidal anhydrous
Magnesium stearate

Capsule shell



54

Titanium dioxide (E171),
Yellow iron oxide (E172),
Red iron oxide (E172)
Gelatine

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 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/Alu-foil): 28, 30, 56, 60 or 112 hard capsules in a box.
HDPE container: 200 or 250 hard capsules in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

28 hard capsules: EU/1/09/525/020
30 hard capsules: EU/1/09/525/021
56 hard capsules: EU/1/09/525/022
60 hard capsules: EU/1/09/525/023
112 hard capsules: EU/1/09/525/024
200 hard capsules: EU/1/09/525/050
250 hard capsules: EU/1/09/525/025

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



55

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg orodispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 1.5 mg rivastigmine. 

Excipient with known effect:
Each orodispersible tablet contains 5.25 µg sorbitol E420.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orodispersible tablet.

The tablets are round and white.

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.

Posology
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.

Nimvastid orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, 
so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. 
Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister.

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. It has the same dosage and frequency of administration as rivastigmine capsules. 
Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine capsules.

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 



56

6 mg twice a day should also be based on good tolerability of the current dose and may be considered 
after a minimum of two weeks of treatment at that dose level.

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or 
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with 
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. 
If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated 
dose or the treatment may be discontinued.

Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should 
be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg 
twice a day.

Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists.
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for 
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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid orodispersible tablets may be used in this patient 
population provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).



57

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



58

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to adverse reactions.

Nimvastid contains sorbitol E420. Patients with rare hereditary problems of fructose intolerance 
should not take this medicine.

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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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.



59

According to its metabolism, metabolic interactions with other medicinal products appear unlikely, 
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.

4.6 Fertility, pregnancy and lactation

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration



60

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.



61

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Common
Not known

Insomnia
Anxiety
Restlessness
Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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



62

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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.



63

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444



64

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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo



65

Patients with visual 
hallucinations

Patients without visual 
hallucinations

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine 
capsules.

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 



66

CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients



67

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.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1 or 112 x 1 tablet in OPA/Alu/PVC foil film and PET/Alu peel off 
foil perforated unit dose blister packs in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

14 x 1 orodispersible tablet:EU/1/09/525/026
28 x 1 orodispersible tablet:EU/1/09/525/027
30 x 1 orodispersible tablet:EU/1/09/525/028
56 x 1 orodispersible tablet:EU/1/09/525/029
60 x 1 orodispersible tablet:EU/1/09/525/030
112 x 1 orodispersible tablet:EU/1/09/525/031

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT



68

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



69

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg orodispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 3 mg rivastigmine. 

Excipient with known effect:
Each orodispersible tablet contains 10.5 µg sorbitol E420.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orodispersible tablet.

The tablets are round and white.

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.

Posology
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.

Nimvastid orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, 
so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. 
Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister.

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. It has the same dosage and frequency of administration as rivastigmine capsules. 
Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine capsules.

Initial dose
1.5 mg twice a day.

Dose titration



70

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.

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid orodispersible tablets may be used in this patient 
population provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 



71

possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



72

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to adverse reactions.

Nimvastid contains sorbitol E420. Patients with rare hereditary problems of fructose intolerance 
should not take this medicine.

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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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 



73

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration



74

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.



75

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Common
Not known

Insomnia
Anxiety
Restlessness
Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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



76

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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.



77

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444



78

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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo



79

Patients with visual 
hallucinations

Patients without visual 
hallucinations

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine 
capsules.

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 



80

CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients



81

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.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

28 x 1, 30 x 1, 56 x 1, 60 x 1 or 112 x 1 tablet in OPA/Alu/PVC foil film and PET/Alu peel off foil 
perforated unit dose blister packs in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/032
30 x 1 orodispersible tablet:EU/1/09/525/033
56 x 1 orodispersible tablet:EU/1/09/525/034
60 x 1 orodispersible tablet:EU/1/09/525/035
112 x 1 orodispersible tablet:EU/1/09/525/036

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT



82

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



83

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg orodispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 4.5 mg rivastigmine. 

Excipient with known effect:
Each orodispersible tablet contains 15.75 µg sorbitol E420.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orodispersible tablet.

The tablets are round and white.

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.

Posology
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.

Nimvastid orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, 
so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. 
Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister.

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. It has the same dosage and frequency of administration as rivastigmine capsules. 
Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine capsules.

Initial dose
1.5 mg twice a day.

Dose titration



84

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.

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid orodispersible tablets may be used in this patient 
population provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 



85

possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



86

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to adverse reactions.

Nimvastid contains sorbitol E420. Patients with rare hereditary problems of fructose intolerance 
should not take this medicine.

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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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 



87

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration



88

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.



89

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Common
Not known

Insomnia
Anxiety
Restlessness
Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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



90

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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.



91

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444



92

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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo



93

Patients with visual 
hallucinations

Patients without visual 
hallucinations

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine 
capsules.

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 



94

CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients



95

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.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

28 x 1, 30 x 1, 56 x 1, 60 x 1 or 112 x 1 tablet in OPA/Alu/PVC foil film and PET/Alu peel off foil 
perforated unit dose blister packs in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/037
30 x 1 orodispersible tablet:EU/1/09/525/038
56 x 1 orodispersible tablet:EU/1/09/525/039
60 x 1 orodispersible tablet:EU/1/09/525/040
112 x 1 orodispersible tablet:EU/1/09/525/041

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT



96

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



97

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg orodispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 6 mg rivastigmine. 

Excipient with known effect:
Each orodispersible tablet contains 21 µg sorbitol E420.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Orodispersible tablet.

The tablets are round and white.

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.

Posology
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.

Nimvastid orodispersible tablet should be placed in the mouth, where it will rapidly disperse in saliva, 
so it can be easily swallowed. Removal of the intact orodispersible tablet from the mouth is difficult. 
Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister.

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. It has the same dosage and frequency of administration as rivastigmine capsules. 
Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine capsules.

Initial dose
1.5 mg twice a day.

Dose titration



98

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.

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 three 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
No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. 
However, due to increased exposure in these populations dosing recommendations to titrate according to 
individual tolerability should be closely followed as patients with clinically significant renal or hepatic 
impairment might experience more dose-dependent adverse reactions. Patients with severe hepatic 
impairment have not been studied, however, Nimvastid orodispersible tablets may be used in this patient 
population provided close monitoring is exercised (see sections 4.4 and 5.2).

Paediatric population
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

4.3 Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity to the active 
substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine 
patch (see section 4.4).

4.4 Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the 



99

possibility of adverse reactions (e.g. vomiting).

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate in 
intensity. These reactions are not in themselves an indication of sensitisation. However, use of 
rivastigmine patch may lead to allergic contact dermatitis.

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch 
size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, 
vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these 
cases, treatment should be discontinued (see section 4.3).

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigmine 
patch and who still require rivastigmine treatment should only be switched to oral rivastigmine after 
negative allergy testing and under close medical supervision. It is possible that some patients 
sensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine in 
any form.

There have been rare post-marketing reports of patients experiencing allergic dermatitis 
(disseminated) when administered rivastigmine irrespective of the route of administration (oral, 
transdermal). In these cases, treatment should be discontinued (see section 4.3).

Patients and caregivers should be instructed accordingly.

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, vomiting and diarrhoea are dose-related, and may occur 
particularly when initiating treatment and/or increasing the dose (see section 4.8). These adverse 
reactions occur more commonly in women. Patients who show signs or symptoms of dehydration 
resulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dose 
reduction or discontinuation if recognised and treated promptly. Dehydration can be associated with 
serious outcomes.

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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de 
pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of 
developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial 
infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant 
use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 
4.5 and 4.8).

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.



100

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.

Special populations
Patients with clinically significant renal or hepatic impairment might experience more adverse reactions 
(see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be 
closely followed. Patients with severe hepatic impairment have not been studied. However, Nimvastid
may be used in this patient population and close monitoring is necessary.

Patients with body weight below 50 kg may experience more adverse reactions and may be more likely 
to discontinue due to adverse reactions.

Nimvastid contains sorbitol E420. Patients with rare hereditary problems of fructose intolerance 
should not take this medicine.

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 and possible additive effects, rivastigmine should not be given 
concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of 
anticholinergic medicinal products (e.g oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with the 
combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta-
blockers are expected to be associated with the greatest risk, but reports have also been received in 
patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is 
combined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmic agents, 
calcium channel antagonists, digitalis glycoside, pilocarpin).

Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the combination of 
rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics i.e. some 
phenothiazines (chlorpromazine, levomepromazine), benzamides (sulpiride, sultopride, amisulpride, 
tiapride, veralipride), pimozide, haloperidol, droperidol, cisapride, citalopram, diphemanil, 
erythromycin IV, halofantrin, mizolastin, methadone, pentamidine and moxifloxacine should be 
observed with caution and clinical monitoring (ECG) may also be required.

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 



101

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

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs 
in humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, an 
increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly 
necessary.

Breast-feeding
In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk. 
Therefore, women on rivastigmine should not breast-feed.

Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in rats (see 
section 5.3). Effects of rivastigmine on human fertility are not known.

4.7 Effects on ability to drive and use machines

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability 
to use 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

Summary of the safety profile
The most commonly reported adverse reactions (ADRs) 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.

Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer’s dementia treated with rivastigmine.

Table 1

Infections and infestations
Very rare Urinary infection
Metabolism and nutritional disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration



102

Psychiatric disorders
Common
Common
Common
Common
Uncommon
Uncommon
Very rare
Not known

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness

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

Not known

Angina pectoris
Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular 
block, atrial fibrillation and tachycardia)
Sick sinus syndrome

Vascular disorders
Very rare Hypertension
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
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue 
disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration
site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common Weight loss

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with 
dementia associated with Parkinson’s disease treated with rivastigmine capsules.



103

Table 2

Metabolism and nutritional disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Common
Not known

Insomnia
Anxiety
Restlessness
Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common
Common
Common
Uncommon

Tremor
Dizziness
Somnolence
Headache
Parkinson’s disease (worsening)
Bradykinesia
Dyskinesia
Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known Hepatitis
Skin and subcutaneous tissue 
disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration
site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

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



104

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate 
poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and 
diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary 
urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures 
and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, 
confusional state, hypertension, hallucinations and malaise.

Management
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.



105

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, 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 (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a 
performance based measure of cognition), the CIBIC-Plus (Clinician’s Interview Based Impression of 
Change-Plus, a comprehensive global assessment of the patient by the physician incorporating 
caregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of the 
activities of daily living including personal hygiene, feeding, dressing, household chores such as 
shopping, retention of ability to orient oneself to surroundings as well as involvement in activities 
relating to finances, etc.).

The patients studied had an MMSE (Mini-Mental State Examination) score of 10-24.

The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer’s Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10% 
improvement on the PDS.

In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6-12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid.

Table 4

Patients with Clinically Significant Response (%)
Intent to Treat Last Observation Carried

Forward
Response Measure Rivastigmine

6-12 mg
N=473

Placebo

N=472

Rivastigmine
6-12 mg
N=379

Placebo

N=444



106

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

Adjusted treatment difference
p-value versus placebo

ITT - LOCF population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

2.881

<0.0011
n/a

0.0072

(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

3.541

<0.0011
n/a

<0.0012
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.
2 Mean data shown for convenience, categorical analysis performed using van Elteren test
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward

Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6).

Table 6

Dementia associated with 
Parkinson's Disease

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo

ADAS-Cog
Rivastigmine

ADAS-Cog
Placebo



107

Patients with visual 
hallucinations

Patients without visual 
hallucinations

ITT + RDO population

Mean baseline ± SD
Mean change at 24 weeks
± SD

Adjusted treatment difference
p-value versus placebo

(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

4.271

0.0021
2.091

0.0151

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

Adjusted treatment difference
p-value versus placebo

(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

4.731

0.0021
2.141

0.0101
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

The European Medicines Agency has waived the obligation to submit the results of studies with 
rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and in 
the treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 for 
information on paediatric use).

5.2 Pharmacokinetic properties

Rivastigmine orodispersible tablet is bioequivalent to rivastigmine capsules, with a similar rate and 
extent of absorption. Rivastigmine orodispersible tablets may be used as an alternative to rivastigmine 
capsules.

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 (tmax) by 90 min and lowers Cmax 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.

Biotranformation
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 in vitro studies, no pharmacokinetic interaction is expected with medicinal products 
metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, 



108

CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from 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.

Elimination
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.

A population pharmacokinetic analysis showed that nicotine use increases the oral clearance of 
rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and 549 non-smokers) 
following rivastigmine oral capsule doses of up to 12 mg/day.

Elderly 
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.

Hepatic impairment
The Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine was more than 
twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Renal impairment
Cmax 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 Cmax 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 104 times the maximum clinical 
exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not 
show a genotoxic potential.

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. In oral studies with male 
and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive 
performance of either the parent generation or the offspring of the parents.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients



109

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.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

28 x 1, 30 x 1, 56 x 1, 60 x 1 or 112 x 1 tablet in OPA/Alu/PVC foil film and PET/Alu peel off foil 
perforated unit dose blister packs in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements for disposal.

7. MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

8. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/042
30 x 1 orodispersible tablet:EU/1/09/525/043
56 x 1 orodispersible tablet:EU/1/09/525/044
60 x 1 orodispersible tablet:EU/1/09/525/045
112 x 1 orodispersible tablet:EU/1/09/525/046

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 11/5/2009
Date of latest renewal: DD month YYYY

10. DATE OF REVISION OF THE TEXT



110

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu



111

ANNEX II

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND 
USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT



112

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

KRKA, d.d., Novo mesto
Šmarješka cesta 6
8501 Novo mesto
Slovenia

The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristic, Section 4.2.)

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

Not applicable.



113

ANNEX III

LABELLING AND PACKAGE LEAFLET



114

A. LABELLING



115

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

CARTON FOR BLISTERS AND CONTAINER, AND LABEL FOR CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg hard capsules

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 1.5 mg rivastigmine.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Hard capsule

Blister:
14 hard capsules
28 hard capsules
30 hard capsules
56 hard capsules
60 hard capsules
112 hard capsules

Container:
200 hard capsules
250 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

To be swallowed whole without crushing or opening.

N
I



116

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 1.5 mg (on carton label only)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

(on carton label only)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA



117

PC:
SN:
NN:

(on carton label only)



118

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg hard capsules

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



119

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

CARTON FOR BLISTERS AND CONTAINER, AND LABEL FOR CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg hard capsules

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 3 mg rivastigmine.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Hard capsule

Blister:
28 hard capsules
30 hard capsules
56 hard capsules
60 hard capsules
112 hard capsules

Container:
200 hard capsules
250 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

To be swallowed whole without crushing or opening.

8. EXPIRY DATE

-J



120

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 3mg (on carton label only)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

(on carton label only)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:



121

NN:

(on carton label only)



122

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg hard capsules

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



123

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

CARTON FOR BLISTERS AND CONTAINER, AND LABEL FOR CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg hard capsules

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 4.5 mg rivastigmine.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Hard capsule

Blister:
28 hard capsules
30 hard capsules
56 hard capsules
60 hard capsules
112 hard capsules

Container:
200 hard capsules
250 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

To be swallowed whole without crushing or opening.

8. EXPIRY DATE

-J



124

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

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

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 4.5 mg (on carton label only)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

(on carton label only)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:



125

NN:

(on carton label only)



126

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg hard capsules

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



127

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING

CARTON FOR BLISTERS AND CONTAINER, AND LABEL FOR CONTAINER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg hard capsules

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 6 mg rivastigmine.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

Hard capsule

Blister:
28 hard capsules
30 hard capsules
56 hard capsules
60 hard capsules
112 hard capsules

Container:
200 hard capsules
250 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

To be swallowed whole without crushing or opening.

8. EXPIRY DATE

-J



128

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

28 hard capsules: EU/1/09/525/020
30 hard capsules: EU/1/09/525/021
56 hard capsules: EU/1/09/525/022
60 hard capsules: EU/1/09/525/023
112 hard capsules: EU/1/09/525/024
200 hard capsules: EU/1/09/525/050
250 hard capsules: EU/1/09/525/025

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 6 mg (on carton label only)

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

(on carton label only)

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:



129

NN:

(on carton label only)



130

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg hard capsules

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER



131

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg orodispersible tablets

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 1.5 mg rivastigmine. 

3. LIST OF EXCIPIENTS

Excipient: sorbitol E420.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Orodispersible tablet

14 x 1 orodispersible tablet
28 x 1 orodispersible tablet
30 x 1 orodispersible tablet
56 x 1 orodispersible tablet
60 x 1 orodispersible tablet
112 x 1 orodispersible tablet

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

Do not handle the tablets with wet hands as the tablets may break up.

1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently 
tearing along the perforations around it,

2. Pull up the edge of the foil and peel foil off completely,
3.Tip the tablet out onto your hand.
4.Put the tablet on the tongue as soon as it is removed from the packaging.

Dissolve the tablet in the mouth and swallow it with or without water.

S4 
___



132

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

14 x 1 orodispersible tablet:EU/1/09/525/026
28 x 1 orodispersible tablet:EU/1/09/525/027
30 x 1 orodispersible tablet:EU/1/09/525/028
56 x 1 orodispersible tablet:EU/1/09/525/029
60 x 1 orodispersible tablet:EU/1/09/525/030
112 x 1 orodispersible tablet:EU/1/09/525/031

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 1.5 mg



133

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



134

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 1.5 mg orodispersible tablets

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

1. Tear.
2. Peel.



135

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg orodispersible tablets

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 3 mg rivastigmine. 

3. LIST OF EXCIPIENTS

Excipient: sorbitol E420.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Orodispersible tablet

28 x 1 orodispersible tablet
30 x 1 orodispersible tablet
56 x 1 orodispersible tablet
60 x 1 orodispersible tablet
112 x 1 orodispersible tablet

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

Do not handle the tablets with wet hands as the tablets may break up.

1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently 
tearing along the perforations around it,

2. Pull up the edge of the foil and peel foil off completely,
3. Tip the tablet out onto your hand.
4. Put the tablet on the tongue as soon as it is removed from the packaging.

Dissolve the tablet in the mouth and swallow it with or without water.

I I

I I

S4 
___



136

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/032
30 x 1 orodispersible tablet:EU/1/09/525/033
56 x 1 orodispersible tablet:EU/1/09/525/034
60 x 1 orodispersible tablet:EU/1/09/525/035
112 x 1 orodispersible tablet:EU/1/09/525/036

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 3 mg



137

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



138

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 3 mg orodispersible tablets

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

1. Tear.
2. Peel.



139

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg orodispersible tablets

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 4.5 mg rivastigmine. 

3. LIST OF EXCIPIENTS

Excipient: sorbitol E420.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Orodispersible tablet

28 x 1 orodispersible tablet
30 x 1 orodispersible tablet
56 x 1 orodispersible tablet
60 x 1 orodispersible tablet
112 x 1 orodispersible tablet

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

Do not handle the tablets with wet hands as the tablets may break up.

1.Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently 
tearing along the perforations around it,
2.Pull up the edge of the foil and peel foil off completely,
3.Tip the tablet out onto your hand.
4.Put the tablet on the tongue as soon as it is removed from the packaging.

Dissolve the tablet in the mouth and swallow it with or without water.

I I

I I

S4 
___



140

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/037
30 x 1 orodispersible tablet:EU/1/09/525/038
56 x 1 orodispersible tablet:EU/1/09/525/039
60 x 1 orodispersible tablet:EU/1/09/525/040
112 x 1 orodispersible tablet:EU/1/09/525/041

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 4.5 mg



141

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



142

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 4.5 mg orodispersible tablets

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

1. Tear.
2. Peel.



143

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg orodispersible tablets

Rivastigmine

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 6 mg rivastigmine. 

3. LIST OF EXCIPIENTS

Excipient: sorbitol E420.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Orodispersible tablet

28 x 1 orodispersible tablet
30 x 1 orodispersible tablet
56 x 1 orodispersible tablet
60 x 1 orodispersible tablet
112 x 1 orodispersible tablet

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.

Do not handle the tablets with wet hands as the tablets may break up.

1. Hold the blister strip at the edges and separate one blister cell from the rest of the strip by gently 
tearing along the perforations around it,

2. Pull up the edge of the foil and peel foil off completely,
3. Tip the tablet out onto your hand.
4. Put the tablet on the tongue as soon as it is removed from the packaging.

Dissolve the tablet in the mouth and swallow it with or without water.

I I

I I

S4 
___



144

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

12. MARKETING AUTHORISATION NUMBER(S)

28 x 1 orodispersible tablet:EU/1/09/525/042
30 x 1 orodispersible tablet:EU/1/09/525/043
56 x 1 orodispersible tablet:EU/1/09/525/044
60 x 1 orodispersible tablet:EU/1/09/525/045
112 x 1 orodispersible tablet:EU/1/09/525/046

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

Nimvastid 6 mg



145

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC:
SN:
NN:



146

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER

1. NAME OF THE MEDICINAL PRODUCT

Nimvastid 6 mg orodispersible tablets

Rivastigmine

2. NAME OF THE MARKETING AUTHORISATION HOLDER

KRKA

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. OTHER

1. Tear.
2. Peel.



147

B. PACKAGE LEAFLET



148

Package leaflet: Information for the user

Nimvastid 1.5 mg hard capsules
Nimvastid 3 mg hard capsules

Nimvastid 4.5 mg hard capsules
Nimvastid 6 mg hard capsules

Rivastigmine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

What is in this leaflet:
1. What Nimvastid is and what it is used for
2. What you need to know before you take Nimvastid
3. How to take Nimvastid
4. Possible side effects
5. How to store Nimvastid
6. Contents of the pack and other information

1. What Nimvastid is and what it is used for

The active substance of Nimvastid is rivastigmine.

Rivastigmine belongs to a class of substances called cholinesterase inhibitors. 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 substance 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, Nimvastid 
allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of 
Alzheimer’s disease and dementia associated with Parkinson’s disease.

Nimvastid is used for the treatment of adult patients with mild to moderately severe Alzheimer’s 
dementia, a progressive brain disorder that gradually affects memory, intellectual ability and 
behaviour. The capsules and oral solution can also be used for the treatment of dementia in adult 
patients with Parkinson’s disease.

2. What you need to know before you take Nimvastid

Do not take Nimvastid
- if you are allergic to rivastigmine (the active substance in Nimvastid) or to any of the other 

ingredients of this medicine (listed in section 6).
- if you have a skin reaction spreading beyond the patch size, if there is a more intense local 

reaction (such as blisters, increasing skin inflammation, swelling) and if it does not improve 
within 48 hours after removal of the transdermal patch.

If this applies to you, tell your doctor and do not take Nimvastid.



149

Warnings and precautions
Talk to your doctor before taking Nimvastid:
- if you have, or have ever had, irregular or slow heartbeat.
- if you have, or have ever had, an active stomach ulcer.
- if you have, or have ever had, difficulties in passing urine.
- if you have, or have ever had, seizures.
- if you have, or have ever had, asthma or severe respiratory disease.
- if you have, or have ever had impaired kidney function.
- if you have, or have ever had, impaired liver function.
- if you suffer from trembling.
- if you have a low body weight.
- if you have gastrointestinal reactions such as feeling sick (nausea), being sick (vomiting) and 

diarrhoea. You may become dehydrated (losing too much fluid) if vomiting or diarrhoea are 
prolonged.

If any of these apply to you, your doctor may need to monitor you more closely while you are on this 
medicine.

If you have not taken Nimvastid for more than three days, do not take the next dose until you have 
talked to your doctor.

Children and adolescents
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

Other medicines and Nimvastid
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.

Nimvastid should not be given at the same time as other medicines with similar effects to Nimvastid. 
Nimvastid might interfere with anticholinergic medicines (medicines used to relieve stomach cramps 
or spasms, to treat Parkinson’s disease or to prevent travel sickness).

Nimvastid should not be given at the same time as metoclopramide (a medicine used to relieve or 
prevent nausea and vomiting). Taking the two medicines together could cause problems such as stiff 
limbs and trembling hands.

If you have to undergo surgery whilst taking Nimvastid, tell your doctor before you are given any 
anaesthetics, because Nimvastid may exaggerate the effects of some muscle relaxants during 
anaesthesia.

Caution when Nimvastid is taken together with beta-blockers (medicines such as atenolol used to treat 
hypertension, angina and other heart conditions). Taking the two medicines together could cause 
problems such as slowing of the heartbeat (bradycardia) leading to fainting or loss of consciousness.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

If you are pregnant, the benefits of using Nimvastid must be assessed against the possible effects on 
your unborn child. Nimvastid should not be used during pregnancy unless clearly necessary.

You should not breast-feed during treatment with Nimvastid.

Driving and using machines
Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. 
Nimvastid may cause dizziness and somnolence, mainly at the start of treatment or when increasing 



150

the dose. If you feel dizzy or sleepy, do not drive, use machines or perform any tasks that require your 
attention.

3. How to take Nimvastid

Always take this medicine exactly as your doctor has told you. Check with your doctor, pharmacist or 
nurse if you are not sure.

How to start treatment
Your doctor will tell you what dose of Nimvastid to take.
 Treatment usually starts with a low dose.
 Your doctor will slowly increase your dose depending on how you respond to treatment.
 The highest dose that should be taken is 6.0 mg twice a day.

Your doctor will regularly check if the medicine is working for you. Your doctor will also monitor 
your weight whilst you are taking this medicine.

If you have not taken Nimvastid for more than three days, do not take the next dose until you have 
talked to your doctor.

Taking this medicine
 Tell your caregiver that you are taking Nimvastid.
 To benefit from your medicine, take it every day.
 Take Nimvastid twice a day, in the morning and evening, with food.
 Swallow the capsules whole with a drink.
 Do not open or crush the capsules.

If you take more Nimvastid than you should
If you accidentally take more Nimvastid than you should, inform your doctor. You may require 
medical attention. Some people who have accidentally taken too much Nimvastid have experienced 
feeling sick (nausea), being sick (vomiting), diarrhoea, high blood pressure and hallucinations. Slow 
heartbeat and fainting may also occur.

If you forget to take Nimvastid
If you find you have forgotten to take your dose of Nimvastid, wait and take the next dose at the usual 
time. Do not take a double dose to make up for a forgotten dose.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You may have side effects more often when you start your medicine or when your dose is increased. 
Usually, the side effects will slowly go away as your body gets used to the medicine.

Very common (may affect more than 1 in 10 people)
 Feeling dizzy
 Loss of appetite
 Stomach problems such as feeling sick (nausea) or being sick (vomiting), diarrhoea

Common (may affect up to 1 in 10 people)
 Anxiety
 Sweating



151

 Headache
 Heartburn
 Weight loss
 Stomach pain
 Feeling agitated
 Feeling tired or weak
 Generally feeling unwell
 Trembling or feeling confused
 Decreased appetite
 Nightmares

Uncommon (may affect up to 1 in 100 people)
 Depression
 Difficulty in sleeping
 Fainting or accidentally falling
 Changes in how well your liver is working

Rare (may affect up to 1 in 1,000 people)
 Chest pain
 Rash, itching
 Fits (seizures)
 Ulcers in your stomach or intestine

Very rare (may affect up to 1 in 10,000 people)
 High blood pressure
 Urinary tract infection
 Seeing things that are not there (hallucinations)
 Problems with your heartbeat such as fast or slow heartbeat
 Bleeding in the gut – shows as blood in stools or when being sick
 Inflammation of the pancreas – the signs include serious upper stomach pain, often with feeling 

sick (nausea) or being sick (vomiting)
 The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, 

difficulty in carrying out movements

Not known (frequency cannot be estimated from the available data)
 Being violently sick (vomiting) that can cause tearing of the tube that connects your mouth with 

your stomach (oesophagus)
 Dehydration (losing too much fluid)
 Liver disorders (yellow skin, yellowing of the whites of the eyes, abnormal darkening of the 

urine or unexplained nausea, vomiting, tiredness and loss of appetite)
 Aggression, feeling restless
 Uneven heartbeat

Patients with dementia and Parkinson’s disease
These patients have some side effects more often. They also have some additional side effects:

Very common (may affect more than 1 in 10 people)
 Trembling
 Fainting
 Accidentally falling

Common (may affect up to 1 in 10 people)
 Anxiety
 Feeling restless
 Slow and fast heartbeat



152

 Difficulty in sleeping
 Too much saliva and dehydration
 Unusually slow movements or movements you cannot control
 The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, 

difficulty in carrying out movements and muscle weakness

Uncommon (may affect up to 1 in 100 people)
 Uneven heartbeat and poor control of movements

Other side effects seen with rivastigmine transdermal patches and which may occur with the 
hard capsules:

Common (may affect up to 1 in 10 people)
 Fever
 Severe confusion
 Urinary incontinence (inability to retain adequate urine)

Uncommon (may affect up to 1 in 100 people)
 Hyperactivity (high level of activity, restlessness)

Not known (frequency cannot be estimated from the available data)
 Allergic reaction where the patch was used, such as blisters or skin inflammation
If you get any of these side effects, contact your doctor as you may need medical assistance.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Nimvastid

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry 
date refers to the last day of that month.

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Nimvastid contains

- The active substance is rivastigmine hydrogen tartrate.
Each hard capsule contains rivastigmine hydrogen tartrate equivalent to 1.5 mg, 3 mg, 4.5 mg or 
6 mg rivastigmine.

- The other ingredients for Nimvastid 1.5 mg capsules are microcrystalline cellulose, 
hypromellose, colloidal anhydrous silica, magnesium stearate in the capsule content, and 
titanium dioxide (E171), yellow iron oxide (E172) and gelatine in the capsule shell.

- The other ingredients for Nimvastid 3 mg, 4.5 mg and 6 mg capsules are microcrystalline 
cellulose, hypromellose, colloidal anhydrous silica, magnesium stearate in the capsule content, 



153

and titanium dioxide (E171), yellow iron oxide (E172), red iron oxide (E172) and gelatine in the 
capsule shell.

What Nimvastid looks like and contents of the pack
Nimvastid 1.5 mg hard capsules, which contain a white to almost white powder, have a yellow cap and 
yellow body.

Nimvastid 3 mg hard capsules, which contain a white to almost white powder, have an orange cap and 
orange body.

Nimvastid 4.5 mg hard capsules, which contain a white to almost white powder, have a brownish red 
cap and brownish red body.

Nimvastid 6 mg hard capsules, which contain a white to almost white powder, have a brownish red 
cap and orange body.

Blister pack (PVC/PVDC/Alu-foil): boxes of 14 (only for 1.5 mg), 28, 30, 56, 60 or 112 hard capsules 
are available.
HDPE container: boxes of 200 or 250 hard capsules are available.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62

Lietuva
UAB KRKA Lietuva
Tel: + 370 5 236 27 40

България
КРКА България ЕООД
Teл.: + 359 (02) 962 34 50

Luxembourg/Luxemburg
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62 (BE)

Česká republika
KRKA ČR, s.r.o.
Tel: + 420 (0) 221 115 150

Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.: + 361 (0) 355 8490

Danmark
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Malta
E.J. Busuttil Ltd.
Tel: +356 21 445 885

Deutschland
TAD Pharma GmbH
Tel: + 49 (0) 4721 606-0

Nederland
KRKA Belgium, SA.
Tel: +32 (0) 487 50 73 62 (BE)

Eesti
KRKA, d.d., Novo mesto Eesti filiaal
Tel: + 372 (0) 6 671 658

Norge
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Ελλάδα
QUALIA PHARMA S.A.
Tηλ: +30 210 6256177

Österreich
KRKA Pharma GmbH, Wien
Tel: + 43 (0)1 66 24 300



154

España
KRKA Farmacéutica, S.L.
Tel: + 34 911 61 03 81

Polska
KRKA-POLSKA Sp. z o.o.
Tel.: + 48 (0)22 573 7500

France
KRKA France Eurl
Tél: + 33 (0)1 57 40 82 25

Portugal
KRKA Farmacêutica, Sociedade Unipessoal Lda.
Tel: + 351 (0)21 46 43 650

Hrvatska
KRKA - FARMA d.o.o.
Tel: + 385 1 6312 100

România
KRKA Romania S.R.L., Bucharest
Tel: + 4 021 310 66 05

Ireland
KRKA Pharma Dublin, Ltd.
Tel: + 353 1 293 91 80

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 Farmaceutici Milano S.r.l.
Tel: + 39 02 3300 8841

Suomi/Finland
KRKA Finland Oy
Puh/Tel: +358 20 754 5330

Κύπρος
Kipa Pharmacal Ltd.
Τηλ: + 357 24 651 882

Sverige
KRKA Sverige AB
Tel: + 46 (0)8 643 67 66 (SE)

Latvija
KRKA Latvija SIA
Tel: + 371 6 733 86 10

United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0) 203 751 1888

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu



155

Package leaflet: Information for the user

Nimvastid 1.5 mg orodispersible tablets
Nimvastid 3 mg orodispersible tablets

Nimvastid 4.5 mg orodispersible tablets
Nimvastid 6 mg orodispersible tablets

Rivastigmine

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4.

In this leaflet:

1. What Nimvastid is and what it is used for
2. What you need to know before you take Nimvastid
3. How to take Nimvastid
4. Possible side effects
5. How to store Nimvastid
6. Contents of the pack and other information

1. What Nimvastid is and what it is used for

The active substance of Nimvastid is rivastigmine.

Rivastigmine belongs to a class of substances called cholinesterase inhibitors. 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 substance 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, Nimvastid 
allows levels of acetylcholine to be increased in the brain, helping to reduce the symptoms of 
Alzheimer’s disease and dementia associated with Parkinson’s disease.

Nimvastid is used for the treatment of adult patients with mild to moderately severe Alzheimer’s 
dementia, a progressive brain disorder that gradually affects memory, intellectual ability and 
behaviour. The capsules and oral solution can also be used for the treatment of dementia in adult 
patients with Parkinson’s disease.

2. What you need to know before you take Nimvastid

Do not take Nimvastid
- if you are allergic to rivastigmine (the active substance in Nimvastid) or to any of the other 

ingredients of this medicine (listed in section 6).
- if you have a skin reaction spreading beyond the patch size, if there is a more intense local 

reaction (such as blisters, increasing skin inflammation, swelling) and if it does not improve 
within 48 hours after removal of the transdermal patch.

If this applies to you, tell your doctor and do not take Nimvastid.



156

Warnings and precautions
Talk to your doctor before taking Nimvastid:
- if you have, or have ever had, irregular or slow heartbeat.
- if you have, or have ever had, an active stomach ulcer.
- if you have, or have ever had, difficulties in passing urine.
- if you have, or have ever had, seizures.
- if you have, or have ever had, asthma or severe respiratory disease.
- if you have, or have ever had impaired kidney function.
- if you have, or have ever had, impaired liver function.
- if you suffer from trembling.
- if you have a low body weight.
- if you have gastrointestinal reactions such as feeling sick (nausea), being sick (vomiting) and 

diarrhoea. You may become dehydrated (losing too much fluid) if vomiting or diarrhoea are 
prolonged.

If any of these apply to you, your doctor may need to monitor you more closely while you are on this 
medicine.

If you have not taken Nimvastid for more than three days, do not take the next dose until you have 
talked to your doctor.

Children and adolescents
There is no relevant use of Nimvastid in the paediatric population in the treatment of Alzheimer’s 
disease.

Other medicines and Nimvastid
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.

Nimvastid should not be given at the same time as other medicines with similar effects to Nimvastid. 
Nimvastid might interfere with anticholinergic medicines (medicines used to relieve stomach cramps 
or spasms, to treat Parkinson’s disease or to prevent travel sickness).

Nimvastid should not be given at the same time as metoclopramide (a medicine used to relieve or 
prevent nausea and vomiting). Taking the two medicines together could cause problems such as stiff 
limbs and trembling hands.

If you have to undergo surgery whilst taking Nimvastid, tell your doctor before you are given any 
anaesthetics, because Nimvastid may exaggerate the effects of some muscle relaxants during 
anaesthesia.

Caution when Nimvastid is taken together with beta-blockers (medicines such as atenolol used to treat 
hypertension, angina and other heart conditions). Taking the two medicines together could cause 
problems such as slowing of the heartbeat (bradycardia) leading to fainting or loss of consciousness.

Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

If you are pregnant, the benefits of using Nimvastid must be assessed against the possible effects on 
your unborn child. Nimvastid should not be used during pregnancy unless clearly necessary.

You should not breast-feed during treatment with Nimvastid.

Driving and using machines
Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely. 
Nimvastid may cause dizziness and somnolence, mainly at the start of treatment or when increasing 



157

the dose. If you feel dizzy or sleepy, do not drive, use machines or perform any tasks that require your 
attention.

Nimvastid contains sorbitol E420
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.

3. How to take Nimvastid

Always take this medicine exactly as your doctor has told you. Check with your doctor, pharmacist or 
nurse if you are not sure.

How to start treatment
Your doctor will tell you what dose of Nimvastid to take.
 Treatment usually starts with a low dose.
 Your doctor will slowly increase your dose depending on how you respond to treatment.
 The highest dose that should be taken is 6.0 mg twice a day.

Your doctor will regularly check if the medicine is working for you. Your doctor will also monitor 
your weight whilst you are taking this medicine.

If you have not taken Nimvastid for more than three days, do not take the next dose until you have 
talked to your doctor.

Taking this medicine
 Tell your caregiver that you are taking Nimvastid.
 To benefit from your medicine, take it every day.
 Take Nimvastid twice a day, once with your breakfast and once with your evening meal. Your 

mouth should be empty before taking the tablet.

Nimvastid orodispersible tablets are fragile. They should not be pushed through the foil in the blister 
pack as this will cause damage to the tablet. Do not handle the tablets with wet hands as the tablets 
may break up. Remove a tablet from the package as follows:

1.Hold the blister at the edges and separate one blister cell from the rest of the blister by gently 
tearing along the perforations around it,

2. Pull up the edge of the foil and peel the foil off completely,
3. Tip the tablet out onto your hand.
4. Put the tablet on the tongue as soon as it is removed from the packaging.

In a few seconds it begins disintegrating in the mouth and subsequently can be swallowed without 
water. The mouth should be empty before placing the tablet on the tongue.

If you take more Nimvastid than you should
If you accidentally take more Nimvastid than you should, inform your doctor. You may require 
medical attention. Some people who have accidentally taken too much Nimvastid have experienced 
feeling sick (nausea), being sick (vomiting), diarrhoea, high blood pressure and hallucinations. Slow 
heartbeat and fainting may also occur.

If you forget to take Nimvastid
If you find you have forgotten to take your dose of Nimvastid, wait and take the next dose at the usual 
time. Do not take a double dose to make up for a forgotten dose.



158

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

You may have side effects more often when you start your medicine or when your dose is increased. 
Usually, the side effects will slowly go away as your body gets used to the medicine.

Very common (may affect more than 1 in 10 people)
 Feeling dizzy
 Loss of appetite
 Stomach problems such as feeling sick (nausea) or being sick (vomiting), diarrhoea

Common (may affect up to 1 in 10 people)
 Anxiety
 Sweating
 Headache
 Heartburn
 Weight loss
 Stomach pain
 Feeling agitated
 Feeling tired or weak
 Generally feeling unwell
 Trembling or feeling confused
 Decreased appetite
 Nightmares

Uncommon (may affect up to 1 in 100 people)
 Depression
 Difficulty in sleeping
 Fainting or accidentally falling
 Changes in how well your liver is working

Rare (may affect up to 1 in 1,000 people)
 Chest pain
 Rash, itching
 Fits (seizures)
 Ulcers in your stomach or intestine

Very rare (may affect up to 1 in 10,000 people)
 High blood pressure
 Urinary tract infection
 Seeing things that are not there (hallucinations)
 Problems with your heartbeat such as fast or slow heartbeat
 Bleeding in the gut – shows as blood in stools or when being sick
 Inflammation of the pancreas – the signs include serious upper stomach pain, often with feeling 

sick (nausea) or being sick (vomiting)
 The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, 

difficulty in carrying out movements

Not known (frequency cannot be estimated from the available data)
 Being violently sick (vomiting) that can cause tearing of the tube that connects your mouth with 



159

your stomach (oesophagus)
 Dehydration (losing too much fluid)
 Liver disorders (yellow skin, yellowing of the whites of the eyes, abnormal darkening of the 

urine or unexplained nausea, vomiting, tiredness and loss of appetite)
 Aggression, feeling restless
 Uneven heartbeat

Patients with dementia and Parkinson’s disease
These patients have some side effects more often. They also have some additional side effects:

Very common (may affect more than 1 in 10 people)
 Trembling
 Fainting
 Accidentally falling

Common (may affect up to 1 in 10 people)
 Anxiety
 Feeling restless
 Slow and fast heartbeat
 Difficulty in sleeping
 Too much saliva and dehydration
 Unusually slow movements or movements you cannot control
 The signs of Parkinson’s disease get worse or getting similar signs – such as stiff muscles, 

difficulty in carrying out movements and muscle weakness

Uncommon (may affect up to 1 in 100 people)
 Uneven heartbeat and poor control of movements

Other side effects seen with rivastigmine transdermal patches and which may occur with the 
orodispersible tablets:

Common (may affect up to 1 in 10 people)
 Fever
 Severe confusion
 Urinary incontinence (inability to retain adequate urine)

Uncommon (may affect up to 1 in 100 people)
 Hyperactivity (high level of activity, restlessness)

Not known (frequency cannot be estimated from the available data)
 Allergic reaction where the patch was used, such as blisters or skin inflammation
If you get any of these side effects, contact your doctor as you may need medical assistance.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine.

5. How to store Nimvastid

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the packaging after EXP. The expiry 
date refers to the last day of that month.



160

This medicinal product does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Nimvastid contains

- The active substance is rivastigmine hydrogen tartrate.
Each orodispersible tablet contains rivastigmine hydrogen tartrate equivalent to 1.5 mg, 3 mg, 
4.5 mg or 6 mg rivastigmine. 

- 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/Alu/PVC foil film and 
PET/Alu peel off foil perforated unit dose blister packs are available.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62

Lietuva
UAB KRKA Lietuva
Tel: + 370 5 236 27 40

България
КРКА България ЕООД
Teл.: + 359 (02) 962 34 50

Luxembourg/Luxemburg
KRKA Belgium, SA.
Tél/Tel: +32 (0) 487 50 73 62 (BE)

Česká republika
KRKA ČR, s.r.o.
Tel: + 420 (0) 221 115 150

Magyarország
KRKA Magyarország Kereskedelmi Kft.
Tel.: + 361 (0) 355 8490

Danmark
KRKA Sverige AB
Tlf: + 46 (0)8 643 67 66 (SE)

Malta
E.J. Busuttil Ltd.
Tel: +356 21 445 885

Deutschland
TAD Pharma GmbH
Tel: + 49 (0) 4721 606-0

Nederland
KRKA Belgium, SA.
Tel: +32 (0) 487 50 73 62 (BE)

Eesti
KRKA, d.d., Novo mesto Eesti filiaal

Norge
KRKA Sverige AB



161

Tel: + 372 (0) 6 671 658 Tlf: + 46 (0)8 643 67 66 (SE)

Ελλάδα
QUALIA PHARMA S.A.
Tηλ: +30 210 6256177

Österreich
KRKA Pharma GmbH, Wien
Tel: + 43 (0)1 66 24 300

España
KRKA Farmacéutica, S.L.
Tel: + 34 911 61 03 81

Polska
KRKA-POLSKA Sp. z o.o.
Tel.: + 48 (0)22 573 7500

France
KRKA France Eurl
Tél: + 33 (0)1 57 40 82 25

Portugal
KRKA Farmacêutica, Sociedade Unipessoal Lda.
Tel: + 351 (0)21 46 43 650

Hrvatska
KRKA - FARMA d.o.o.
Tel: + 385 1 6312 100

România
KRKA Romania S.R.L., Bucharest
Tel: + 4 021 310 66 05

Ireland
KRKA Pharma Dublin, Ltd.
Tel: + 353 1 293 91 80

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 Farmaceutici Milano S.r.l.
Tel: + 39 02 3300 8841

Suomi/Finland
KRKA Finland Oy
Puh/Tel: +358 20 754 5330

Κύπρος
Kipa Pharmacal Ltd.
Τηλ: + 357 24 651 882

Sverige
KRKA Sverige AB
Tel: + 46 (0)8 643 67 66 (SE)

Latvija
KRKA Latvija SIA
Tel: + 371 6 733 86 10

United Kingdom
Consilient Health (UK) Ltd.
Tel: + 44 (0) 203 751 1888

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET