Rivastigmine Teva

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 1.5 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule 
 
White cap imprinted with “R” & white body imprinted with “1.5” 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. 
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s 
disease. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by a physician experienced in the diagnosis and 
treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should 
be made according to current guidelines. Therapy with rivastigmine should only be started if a 
caregiver is available who will regularly monitor intake of the medicinal product by the patient. 
 
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.  
 
Initial dose:  
1.5 mg twice a day. 
 
Dose titration  
The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of 
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 
6 mg twice a day should also be based on good tolerability of the current dose and may be considered 
after a minimum of two weeks of treatment at that dose level.   
 
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or 
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with 
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. 
If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated 
dose or the treatment may be discontinued. 

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Maintenance dose  
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should 
be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg 
twice a day. 
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for 
patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment 
the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be 
discontinued.  Discontinuation should also be considered when evidence of a therapeutic effect is no 
longer present. 
 
Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen 
in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in 
Parkinson’s disease patients with visual hallucinations (see section 5.1).  
 
Treatment effect has not been studied in placebo-controlled trials beyond 6 months. 
 
Re-initiation of therapy:  
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. 
Dose titration should then be carried out as described above. 
 
Renal and hepatic impairment:  
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 adverse reactions (see sections 4.4 and 5.2). 
 
Patients with severe hepatic impairment have not been studied (see section 4.4).  
 
Children:  
Rivastigmine is not recommended for use in children. 
 
4.3 Contraindications 
 
The use of this medicinal product is contraindicated in patients with 
- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients 

used in the formulation, 
 
4.4 Special warnings and precautions for use 
 
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).  
 
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's 
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia 
associated with Parkinson's disease) have been observed shortly after dose increase. They may respond 
to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).  
 
Gastrointestinal disorders such as nausea, 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. 
 

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Patients with Alzheimer's disease may lose weight. Cholinesterase inhibitors, including rivastigmine, 
have been associated with weight loss in these patients. During therapy patient's weight should be 
monitored.  
 
In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as 
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments 
or high doses of rivastigmine.  
 
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction 
defects (sino-atrial block, atrio-ventricular block) (see section 4.8).  
 
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients 
with active gastric or duodenal ulcers or patients predisposed to these conditions.  
 
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or 
obstructive pulmonary disease.  
 
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended 
in treating patients predisposed to such diseases.  
 
The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with 
Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related 
cognitive decline) has not been investigated and therefore use in these patient populations is not 
recommended. 
 
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. 
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or 
severity of tremor have been observed in patients with dementia associated with Parkinson's disease 
(see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. 
discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is 
recommended for these adverse reactions. 
 
Special Populations 
Patients with clinically significant renal or hepatic impairment might experience more adverse 
reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. 
However, Rivastigmine Teva 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, rivastigmine should not be given concomitantly with other 
cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.  
 
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam 
or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is 
not affected by administration of rivastigmine. No untoward effects on cardiac conduction were 
observed following concomitant administration of digoxin and rivastigmine.  
 
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, 
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.  

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4.6 Fertility, pregnancy and lactation 
 
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or 
embryofoetal development were observed in rats and rabbits, except at doses related to maternal 
toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine 
should not be used during pregnancy unless clearly necessary.  
 
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human 
milk. Therefore, women on rivastigmine should not breast-feed 
 
4.7 Effects on ability to drive and use machines 
 
Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability 
to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when 
initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate 
influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on 
rivastigmine to continue driving or operating complex machines should be routinely evaluated by the 
treating physician. 
 
4.8 Undesirable effects 
 
The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and 
vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more 
susceptible than male patients to gastrointestinal adverse reactions and weight loss.  
 
The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer's dementia treated with rivastigmine.  
 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency 
category. Frequency categories are defined using the following convention: very common (≥1/10); 
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare 
(<1/10,000); not known (cannot be estimated from the available data). 
 
Table 1  
 
Infections and infestations  

Very rare Urinary infection 

Metabolism and nutrition disorders  

Very common Anorexia 

Not known Dehydration 

Psychiatric disorders  

Common Agitation 

Common Confusion 

Common Anxiety 

Uncommon Insomnia 

Uncommon Depression 

Very rare Hallucinations 

Not known Aggression, restlessness 

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Nervous system disorders  

Very common Dizziness 

Common Headache 

Common Somnolence 

Common Tremor 

Uncommon Syncope 

Rare Seizures 

Very rare Extrapyramidal symptoms (including worsening of 
Parkinson's disease) 

Cardiac disorders  

Rare Angina pectoris 

Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, 
atrial fibrillation and tachycardia) 

Not known Sick sinus syndrome 

Vascular Disorders  

Very rare Hypertension 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Very common Diarrhoea 

Common Abdominal pain and dyspepsia 

Rare Gastric and duodenal ulcers 

Very rare Gastrointestinal haemorrhage 

Very rare Pancreatitis 

Not known Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.4). 

Hepatobiliary disorders  

Uncommon Elevated liver function tests 

Not known Hepatitis 

Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

Rare Rash 

Not known Pruritus 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Malaise 

Uncommon Fall 

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Investigations  

Common Weight loss 

 
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s 
disease treated with rivastigmine.   
 
Table 2 
 
Metabolism and nutrition disorders  

Common Anorexia 

Common Dehydration 

Psychiatric disorders  

Common Insomnia 

Common Anxiety 

Common Restlessness 

Not known Aggression 

Nervous system disorders  

Very common Tremor 

Common Dizziness 

Common Somnolence 

Common Headache 

Common Worsening of Parkinson’s disease 

Common Bradykinesia 

Common Dyskinesia 

Uncommon Dystonia 

Cardiac disorders  

Common Bradycardia 

Uncommon Atrial fibrillation 

Uncommon Atrioventricular block 

Not known Sick sinus syndrome 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Common Diarrhoea 

Common Abdominal pain and dyspepsia 

Common Salivary hypersecretion 

Hepatobiliary disorders  

Not known  Hepatitis 

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Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

Musculoskeletal and connective 
tissue disorders 

 

Common Muscle rigidity 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Gait abnormality 

 
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted 
with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined 
adverse events that may reflect worsening of parkinsonian symptoms.  
 
Table 3 
 
Pre-defined adverse events that may reflect 
worsening of parkinsonian symptoms in 
patients with dementia associated with 
Parkinson's disease 

Rivastigmine 
 
n (%) 

Placebo 
 
n (%) 

Total patients studied 362 (100) 179 (100) 

Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) 

Tremor 37 (10.2) 7 (3.9) 

Fall 21 (5.8) 11 (6.1) 

Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) 

Salivary hypersecretion 5 (1.4) 0 

Dyskinesia 5 (1.4) 1 (0.6) 

Parkinsonism 8 (2.2) 1 (0.6) 

Hypokinesia 1 (0.3) 0 

Movement disorder 1 (0.3) 0 

Bradykinesia 9 (2.5) 3 (1.7) 

Dystonia 3 (0.8) 1 (0.6) 

Gait abnormality 5 (1.4) 0 

Muscle rigidity 1 (0.3) 0 

Balance disorder 3 (0.8) 2 (1.1) 

Musculoskeletal stiffness 3 (0.8) 0 

Rigors 1 (0.3) 0 

Motor dysfunction 1 (0.3) 0 

 
4.9 Overdose 
 
Symptoms 

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Most cases of accidental overdose have not been associated with any clinical signs or symptoms and 
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have 
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to 
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may 
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient 
fully recovered within 24 hours. 
 
Treatment 
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition 
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of 
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea 
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse 
reactions should be given as necessary. 
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate 
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote 
is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 
 
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to 
facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by 
functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on 
cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and 
Parkinson's disease. 
  
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that 
temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases 
acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after 
administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum 
inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF 
by rivastigmine was dose-dependent up to 6  mg given twice daily, the highest dose tested. Inhibition 
of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar 
to that of AChE. 
 
Clinical studies in Alzheimer's dementia 
The efficacy of rivastigmine has been established through the use of three independent, domain 
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. 
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a 
comprehensive global assessment of the patient by the physician incorporating caregiver input), and 
the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, 
feeding, dressing, household chores such as shopping, retention of ability to orient oneself to 
surroundings as well as involvement in activities relating to finances, etc.). 
 
The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. 
 
The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % 
improvement on the PDS. 

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

 Intent to Treat Last Observation Carried 
Forward 

Response Measure Rivastigmine 
6–12 mg 
N=473 

Placebo 
N=472 

Rivastigmine 
6–12 mg 
N=379 

Placebo 
N=444 

ADAS-Cog: improvement of at 
least 4 points 

21*** 12 25*** 12 

CIBIC-Plus: improvement 29*** 18 32*** 19 

PDS: improvement of at least 
10% 

26*** 17 30*** 18 

At least 4 points improvement 
on ADAS-Cog with no 
worsening on CIBIC-Plus and 
PDS 

10* 6 12** 6 

*p<0.05, **p<0.01, ***p<0.001 
 
Clinical studies in dementia associated with Parkinson's disease 
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in 
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label 
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score 
of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at 
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a 
measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-
Clinician's Global Impression of Change). 
 
Table 5 
 
Dementia associated 
with Parkinson's Disease 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADCS-CGIC 
Rivastigmine 

ADCS-CGIC 
Placebo 

ITT + RDO population (n=329) (n=161) (n=329) (n=165) 

Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a 

Mean change at 24 weeks 
± SD 

2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 

Adjusted treatment 
difference 

2.881 n/a 

p-value versus placebo <0.0011 0.0072 

ITT - LOCF population (n=287) (n=154) (n=289) (n=158) 

Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a 

Mean change at 24 weeks 
± SD 

2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 

Adjusted treatment 3.541 n/a 

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difference 

p-value versus placebo <0.0011 <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 

ITT + RDO population (n=107) (n=60) (n=220) (n=101) 

Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 

Mean change at 24 weeks 
± SD 

1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 

Adjusted treatment 
difference 

4.271 2.091 

p-value versus placebo 0.0021 0.0151 

 Patients with moderate dementia 
(MMSE 10-17) 

Patients with mild dementia 
(MMSE 18-24) 

ITT + RDO population (n=87) (n=44) (n=237) (n=115) 

Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 

Mean change at 24 weeks 
± SD 

2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 

Adjusted treatment 
difference 

4.731 2.141 

p-value versus placebo 0.0021 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 
 
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. 
 

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Metabolism 
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), 
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this 
metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro 
and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine 
metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg 
intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. 
 
Excretion 
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route 
of elimination. Following administration of 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. 
 
Elderly subjects  
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in 
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. 
 
Subjects with hepatic impairment  
The 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. 
 
Subjects with 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. 
 
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, 
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When 
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately 
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the 
maximum human dose, a multiple of approximately 6-fold was achieved in animals. 
 
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats 
and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Microcrystalline cellulose  
Hypromellose 
Colloidal silicon dioxide 

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Magnesium stearate 
 
Capsule shell 
Titanium dioxide (E171) 
Gelatin 
Ink used for imprinting - Black S-1-17822/S-1-17823:  
Shellac glaze-45% 
Iron oxide black   
Ammonium hydroxide 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 

- HDPE tablet container with a polypropylene cap and induction seal: 250 capsules 
- 28, 56 or 112 capsules in transparent PVC/Alu push through blisters 
- 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters 

 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/001 
EU/1/09/513/002 
EU/1/09/513/003 
EU/1/09/513/004 
EU/1/09/513/005 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17/04/2009 
 
 
10. DATE OF REVISION OF THE TEXT 

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

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http://www.ema.europa.eu/


1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 3 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule 
 
Flesh colour cap imprinted with “R” & flesh color body imprinted with “3” 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. 
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s 
disease. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by a physician experienced in the diagnosis and 
treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should 
be made according to current guidelines. Therapy with rivastigmine should only be started if a 
caregiver is available who will regularly monitor intake of the medicinal product by the patient. 
 
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.  
 
Initial dose 
1.5 mg twice a day. 
 
Dose titration 
The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of 
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 
6 mg twice a day should also be based on good tolerability of the current dose and may be considered 
after a minimum of two weeks of treatment at that dose level. 
 
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or 
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with 
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. 
If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated 
dose or the treatment may be discontinued. 
 
Maintenance dose 
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should 
be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg 
twice a day. 
Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for 

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patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment 
the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be 
discontinued.  Discontinuation should also be considered when evidence of a therapeutic effect is no 
longer present. 
 
Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen 
in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in 
Parkinson’s disease patients with visual hallucinations (see section 5.1).  
 
Treatment effect has not been studied in placebo-controlled trials beyond 6 months. 
 
Re-initiation of therapy  
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. 
Dose titration should then be carried out as described above. 
 
Renal and hepatic impairment  
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 adverse reactions (see sections 4.4 and 5.2). 
 
Patients with severe hepatic impairment have not been studied (see section 4.4)  
 
Children  
Rivastigmine is not recommended for use in children. 
 
4.3 Contraindications 
 
The use of this medicinal product is contraindicated in patients with 

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients 
used in the formulation, 

 
4.4 Special warnings and precautions for use 
 
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).  
 
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's 
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia 
associated with Parkinson's disease) have been observed shortly after dose increase. They may respond 
to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).  
 
Gastrointestinal disorders such as nausea, 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 

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oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments 
or high doses of rivastigmine.  
 
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction 
defects (sino-atrial block, atrio-ventricular block) (see section 4.8).  
 
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients 
with active gastric or duodenal ulcers or patients predisposed to these conditions.  
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or 
obstructive pulmonary disease.  
 
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended 
in treating patients predisposed to such diseases.  
 
The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with 
Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related 
cognitive decline) has not been investigated and therefore use in these patient populations is not 
recommended.  
  
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. 
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or 
severity of tremor have been observed in patients with dementia associated with Parkinson's disease 
(see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. 
discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is 
recommended for these adverse reactions. 
 
Special Populations 
Patients with clinically significant renal or hepatic impairment might experience more adverse 
reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. 
However, Rivastigmine Teva 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 recomemended when selecting anaesthetic agents. Possible 
dose adjustments or temporarily stopping treatment can be considered if needed.  
 
In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other 
cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.  
 
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam 
or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is 
not affected by administration of rivastigmine. No untoward effects on cardiac conduction were 
observed following concomitant administration of digoxin and rivastigmine.  
 
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, 
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 
 
4.6 Fertility, pregnancy and lactation 
 
For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or 
embryofoetal development were observed in rats and rabbits, except at doses related to maternal 
toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine 
should not be used during pregnancy unless clearly necessary.  

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In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human 
milk. Therefore, women on rivastigmine should not breast-feed 
 
4.7 Effects on ability to drive and use machines 
 
Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability 
to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when 
initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate 
influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on 
rivastigmine to continue driving or operating complex machines should be routinely evaluated by the 
treating physician. 
 
4.8 Undesirable effects 
 
The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and 
vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more 
susceptible than male patients to gastrointestinal adverse reactions and weight loss.  
 
The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer's dementia treated with rivastigmine.  
 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency 
category. Frequency categories are defined using the following convention: very common (≥1/10); 
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare 
(<1/10,000); not known (cannot be estimated from the available data). 
 
Table 1 * 
 
Infections and infestations  

Very rare Urinary infection 

Metabolism and nutrition disorders  

Very common Anorexia 

Not known Dehydration 

Psychiatric disorders  

Common Agitation 

Common Confusion 

Common Anxiety 

Uncommon Insomnia 

Uncommon Depression 

Very rare Hallucinations 

Not known Aggression, restlessness 

Nervous system disorders  

Very common Dizziness 

Common Headache 

Common Somnolence 

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Common Tremor 

Uncommon Syncope 

Rare Seizures 

Very rare Extrapyramidal symptoms (including worsening of 
Parkinson's disease) 

Cardiac disorders  

Rare Angina pectoris 

Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, 
atrial fibrillation and tachycardia) 

Not known  Sick sinus syndrome 

Vascular Disorders  

Very rare Hypertension 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Very common Diarrhoea 

Common Abdominal pain and dyspepsia 

Rare Gastric and duodenal ulcers 

Very rare Gastrointestinal haemorrhage 

Very rare Pancreatitis 

Not known Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.4). 

Hepatobiliary disorders  

Uncommon Elevated liver function tests 

Not known Hepatitis 

Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

Rare Rash 

Not known Pruritus 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Malaise 

Uncommon Fall 

Investigations  

Common Weight loss 

 
Table 2 shows the adverse reactions reported in patients with dementia associated with Parkison’s 
disease treated with rivastigmine.   

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Table 2 
 
Metabolism and nutrition disorders  

Common Anorexia 

Common Dehydration 

Psychiatric disorders  

Common Insomnia 

Common Anxiety 

Common Restlessness 

Not known Aggression 

Nervous system disorders  

Very common Tremor 

Common Dizziness 

Common Somnolence 

Common Headache 

Common Worsening of Parkinson’s disease 

Common Bradykinesia 

Common Dyskinesia 

Uncommon Dystonia 

Cardiac disorders  

Common Bradycardia 

Uncommon Atrial fibrillation 

Uncommon Atrioventricular block 

Not known Sick sinus syndrome 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Common Diarrhoea 

Common Abdominal pain and dyspepsia 

Common Salivary hypersecretion 

Hepatobililary disorders  

Not known Heptatitis 

Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

Musculoskeletal and connective 
tissue disorders 

 

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Common Muscle rigidity 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Gait abnormality 

 
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted 
with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined 
adverse events that may reflect worsening of parkinsonian symptoms.  
 
Table 3 
 
Pre-defined adverse events that may reflect 
worsening of parkinsonian symptoms in 
patients with dementia associated with 
Parkinson's disease 

Rivastigmine 
 
n (%) 

Placebo 
 
n (%) 

Total patients studied 362 (100) 179 (100) 

Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) 

Tremor 37 (10.2) 7 (3.9) 

Fall 21 (5.8) 11 (6.1) 

Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) 

Salivary hypersecretion 5 (1.4) 0 

Dyskinesia 5 (1.4) 1 (0.6) 

Parkinsonism 8 (2.2) 1 (0.6) 

Hypokinesia 1 (0.3) 0 

Movement disorder 1 (0.3) 0 

Bradykinesia 9 (2.5) 3 (1.7) 

Dystonia 3 (0.8) 1 (0.6) 

Gait abnormality 5 (1.4) 0 

Muscle rigidity 1 (0.3) 0 

Balance disorder 3 (0.8) 2 (1.1) 

Musculoskeletal stiffness 3 (0.8) 0 

Rigors 1 (0.3) 0 

Motor dysfunction 1 (0.3) 0 

 
4.9 Overdose 
 
Symptoms  
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and 
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have 
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to 
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may 
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient 
fully recovered within 24 hours. 

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Treatment  
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition 
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of 
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea 
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse 
reactions should be given as necessary. 
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate 
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote 
is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 
 
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to 
facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by 
functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on 
cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and 
Parkinson's disease. 
  
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that 
temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases 
acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after 
administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum 
inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF 
by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition 
of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar 
to that of AChE. 
 
Clinical studies in Alzheimer's dementia 
The efficacy of rivastigmine has been established through the use of three independent, domain 
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. 
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a 
comprehensive global assessment of the patient by the physician incorporating caregiver input), and 
the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, 
feeding, dressing, household chores such as shopping, retention of ability to orient oneself to 
surroundings as well as involvement in activities relating to finances, etc.). 
 
The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. 
 
The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % 
improvement on the PDS. 
 
In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6–12 mg 
group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in this 
indication vary and direct comparisons of results for different therapeutic agents are not valid. 

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Table 4 
 
 Patients with Clinically Significant Response (%) 

 Intent to Treat Last Observation Carried 
Forward 

Response Measure Rivastigmine 
6–12 mg 
N=473 

Placebo 
N=472 

Rivastigmine 
6–12 mg 
N=379 

Placebo 
N=444 

ADAS-Cog: improvement of at 
least 4 points 

21*** 12 25*** 12 

CIBIC-Plus: improvement 29*** 18 32*** 19 

PDS: improvement of at least 
10% 

26*** 17 30*** 18 

At least 4 points improvement 
on ADAS-Cog with no 
worsening on CIBIC-Plus and 
PDS 

10* 6 12** 6 

*p<0.05, **p<0.01, ***p<0.001 
 
Clinical studies in dementia associated with Parkinson's disease 
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in 
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label 
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score 
of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at 
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a 
measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-
Clinician's Global Impression of Change). 
 
Table 5 
 
Dementia associated 
with Parkinson's Disease 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADCS-CGIC 
Rivastigmine 

ADCS-CGIC 
Placebo 

ITT + RDO population (n=329) (n=161) (n=329) (n=165) 

Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a 

Mean change at 24 weeks 
± SD 

2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 

Adjusted treatment 
difference 

2.881 n/a 

p-value versus placebo <0.0011 0.0072 

ITT - LOCF population (n=287) (n=154) (n=289) (n=158) 

Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a 

Mean change at 24 weeks 
± SD 

2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 

Adjusted treatment 
difference 

3.541 n/a 

p-value versus placebo <0.0011 <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 

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

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

 Patients with visual 
hallucinations 

Patients without visual 
hallucinations 

ITT + RDO population (n=107) (n=60) (n=220) (n=101) 

Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 

Mean change at 24 weeks 
± SD 

1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 

Adjusted treatment 
difference 

4.271 2.091 

p-value versus placebo 0.0021 0.0151 

 Patients with moderate dementia 
(MMSE 10-17) 

Patients with mild dementia 
(MMSE 18-24) 

ITT + RDO population (n=87) (n=44) (n=237) (n=115) 

Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 

Mean change at 24 weeks 
± SD 

2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 

Adjusted treatment 
difference 

4.731 2.141 

p-value versus placebo 0.0021 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 
 
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. 
 
Metabolism: 
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), 
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this 
metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro 
and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine 
metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg 
intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. 

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Excretion:  
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. 
 
Elderly subjects:  
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in 
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. 
 
Subjects with hepatic impairment:  
The 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. 
 
Subjects with 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. 
 
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, 
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When 
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately 
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the 
maximum human dose, a multiple of approximately 6-fold was achieved in animals. 
 
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats 
and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Microcrystalline cellulose  
Hypromellose 
Colloidal silicon dioxide 
Magnesium stearate 
 
Capsule shell 
Red iron oxide (E 172) 
Yellow iron oxide (E 172) 
Titanium dioxide (E 171) 
Gelatin 

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Ink used for imprinting - Black S-1-17822/S-1-17823 
Shellac glaze-45%       
Iron oxide black   
Ammonium hydroxide     
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions 
 
6.5 Nature and contents of container 
 

- HDPE tablet container with a polypropylene cap and induction seal: 250 capsules 
- 28, 56 or 112 capsules in transparent PVC/Alu push through blisters  
- 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters 

 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/006 
EU/1/09/513/007 
EU/1/09/513/008 
EU/1/09/513/009 
EU/1/09/513/010 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17/04/2009 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu 
 
 

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http://www.ema.europa.eu/


 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 4.5 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg 

For a full list of excipients, see section 6.1. 

 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule  
 
Orange colour cap imprinted with “R” & orange color body imprinted with “4.5” 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. 
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s 
disease. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by a physician experienced in the diagnosis and 
treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should 
be made according to current guidelines. Therapy with rivastigmine should only be started if a 
caregiver is available who will regularly monitor intake of the medicinal product by the patient. 
 
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.  
 
Initial dose:  
1.5 mg twice a day. 
 
Dose titration:  
The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of 
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 
6 mg twice a day should also be based on good tolerability of the current dose and may be considered 
after a minimum of two weeks of treatment at that dose level. 
 
If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or 
worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with 
Parkinson’s disease are observed during treatment, these may respond to omitting one or more doses. 
If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated 
dose or the treatment may be discontinued. 
 
Maintenance dose:  
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should 
be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg 
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Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. 
Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for 
patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment 
the patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should be 
discontinued.  Discontinuation should also be considered when evidence of a therapeutic effect is no 
longer present. 
 
Individual response to rivastigmine cannot be predicted. However a greater treatment effect was seen 
in Parkinson’s disease patients with moderate dementia. Similarly a larger effect was observed in 
Parkinson’s disease patients with visual hallucinations (see section 5.1). 
 
Treatment effect has not been studied in placebo-controlled trials beyond 6 months. 
 
Re-initiation of therapy:  
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. 
Dose titration should then be carried out as described above. 
 
Renal and hepatic impairment:  
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 adverse reactions (see sections 4.4 and 5.2). 
 
Patients with severe hepatic impairment have not been studied (see section 4.4).  
 
Children:  
Rivastigmine is not recommended for use in children. 
 
4.3 Contraindications 
 
The use of this medicinal product is contraindicated in patients with 

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients 
used in the formulation, 

 
4.4 Special warnings and precautions for use 
 
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).  
 
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's 
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia 
associated with Parkinson's disease) have been observed shortly after dose increase. They may respond 
to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).  
 
Gastrointestinal disorders such as nausea, 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.  
 

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In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as 
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments 
or high doses of rivastigmine.  
 
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction 
defects (sino-atrial block, atrio-ventricular block) (see section 4.8).  
 
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients 
with active gastric or duodenal ulcers or patients predisposed to these conditions.  
 
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or 
obstructive pulmonary disease.  
 
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended 
in treating patients predisposed to such diseases.  
 
 The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with 
Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related 
cognitive decline) has not been investigated and therefore the use in these patient populations is not 
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). Patients with severe hepatic impairment have not been studied. 
However, Rivastigmine Teva 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, rivastigmine should not be given concomitantly with other 
cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.  
 
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam 
or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is 
not affected by administration of rivastigmine. No untoward effects on cardiac conduction were 
observed following concomitant administration of digoxin and rivastigmine.  
 
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, 
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances. 
 
4.6 Fertility, pregnancy and lactation 
 

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For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or 
embryofoetal development were observed in rats and rabbits, except at doses related to maternal 
toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine 
should not be used during pregnancy unless clearly necessary.  
 
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human 
milk. Therefore, women on rivastigmine should not breast-feed 
 
4.7 Effects on ability to drive and use machines 
 
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 machinges. Therefore, the ability of patients with dementia on 
rivastigmine to continue driving or operating complex machines should be routinely evaluated by the 
treating physician. 
 
4.8 Undesirable effects 
 
The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and 
vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more 
susceptible than male patients to gastrointestinal adverse reactions and weight loss.  
 
The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer's dementia treated with rivastigmine.  
 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency 
category. Frequency categories are defined using the following convention: very common (≥1/10); 
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare 
(<1/10,000); not known (cannot be estimated from the available data)  
 
Table 1  
 
Infections and infestations  

Very rare Urinary infection 

Metabolism and nutrition disorders  

Very common Anorexia 

Not known Dehydration 

Psychiatric disorders  

Common Agitation 

Common Confusion 

Common Anxiety 

Uncommon Insomnia 

Uncommon Depression 

Very rare Hallucinations 

Not known Aggression, restlessness 

Nervous system disorders  

Very common Dizziness 

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Common Headache 

Common Somnolence 

Common Tremor 

Uncommon Syncope 

Rare Seizures 

Very rare Extrapyramidal symptoms (including worsening of 
Parkinson's disease) 

Cardiac disorders  

Rare Angina pectoris 

Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, 
atrial fibrillation and tachycardia) 

Not known Sick-sinus syndrome 

Vascular Disorders  

Very rare Hypertension 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Very common Diarrhoea 

Common Abdominal pain and dyspepsia 

Rare Gastric and duodenal ulcers 

Very rare Gastrointestinal haemorrhage 

Very rare Pancreatitis 

Not known Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.4). 

Hepato-biliary disorders  

Uncommon Elevated liver function tests 

Not known Hepatitis 

Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

Rare Rash 

Not known Pruritus 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Malaise 

Uncommon Fall 

Investigations  

Common Weight loss 

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Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s 
disease treated with rivastigmine.  
 
Table 2 
 
Metabolism and nutrition disorders  

Common Anorexia 

Common Dehydration 

Psychiatric disorders  

Common Insomnia 

Common Anxiety 

Common Restlessness 

Not known Aggression 

Nervous system disorders  

Very common Tremor 

Common Dizziness 

Common Somnolence 

Common Headache 

Common Worsening of Parkinson’s disease 

Common Bradykinesia 

Common Dyskinesia 

Uncommon Dystonia 

Cardiac disorders  

Common Bradycardia 

Uncommon Atrial fibrillation 

Uncommon Atrioventricular block 

Not known Sick sinus syndrome 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Common Diarrhoea 

Common Abdominal pain and dyspepsia 

Common Salivary hypersecretion 

Hepatobiliary disorders  

Not known Hepatitis 

Skin and subcutaneous tissue 
disorders 

 

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Common Hyperhydrosis 

Musculoskeletal and connective 
tissue disorders 

 

Common Muscle rigidity 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Gait abnormality 

 
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted 
with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined 
adverse events that may reflect worsening of parkinsonian symptoms.  
 
Table 3 
 
Pre-defined adverse events that may reflect 
worsening of parkinsonian symptoms in 
patients with dementia associated with 
Parkinson's disease 

Rivastigmine 
 
n (%) 

Placebo 
 
n (%) 

Total patients studied 362 (100) 179 (100) 

Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) 

Tremor 37 (10.2) 7 (3.9) 

Fall 21 (5.8) 11 (6.1) 

Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) 

Salivary hypersecretion 5 (1.4) 0 

Dyskinesia 5 (1.4) 1 (0.6) 

Parkinsonism 8 (2.2) 1 (0.6) 

Hypokinesia 1 (0.3) 0 

Movement disorder 1 (0.3) 0 

Bradykinesia 9 (2.5) 3 (1.7) 

Dystonia 3 (0.8) 1 (0.6) 

Gait abnormality 5 (1.4) 0 

Muscle rigidity 1 (0.3) 0 

Balance disorder 3 (0.8) 2 (1.1) 

Musculoskeletal stiffness 3 (0.8) 0 

Rigors 1 (0.3) 0 

Motor dysfunction 1 (0.3) 0 

 
4.9 Overdose 
 
Symptoms  
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and 
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have 

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occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to 
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may 
also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient 
fully recovered within 24 hours. 
 
Treatment 
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition 
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of 
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea 
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse 
reactions should be given as necessary. 
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate 
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote 
is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: anticholinesterases, ATC code: N06DA03 
 
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to 
facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by 
functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on 
cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and 
Parkinson's disease. 
  
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that 
temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases 
acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after 
administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum 
inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF 
by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition 
of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar 
to that of AChE. 
 
Clinical studies in Alzheimer's dementia 
The efficacy of rivastigmine has been established through the use of three independent, domain 
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. 
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a 
comprehensive global assessment of the patient by the physician incorporating caregiver input), and 
the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, 
feeding, dressing, household chores such as shopping, retention of ability to orient oneself to 
surroundings as well as involvement in activities relating to finances, etc.). 
 
The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. 
 
The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % 
improvement on the PDS. 
 

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

 Intent to Treat Last Observation Carried 
Forward 

Response Measure Rivastigmine 
6–12 mg 
N=473 

Placebo 
N=472 

Rivastigmine 
6–12 mg 
N=379 

Placebo 
N=444 

ADAS-Cog: improvement of at 
least 4 points 

21*** 12 25*** 12 

CIBIC-Plus: improvement 29*** 18 32*** 19 

PDS: improvement of at least 
10% 

26*** 17 30*** 18 

At least 4 points improvement 
on ADAS-Cog with no 
worsening on CIBIC-Plus and 
PDS 

10* 6 12** 6 

*p<0.05, **p<0.01, ***p<0.001 
 
Clinical studies in dementia associated with Parkinson's disease 
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in 
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label 
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score 
of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at 
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a 
measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-
Clinician's Global Impression of Change). 
 
Table 5 
 
Dementia associated 
with Parkinson's Disease 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADCS-CGIC 
Rivastigmine 

ADCS-CGIC 
Placebo 

ITT + RDO population (n=329) (n=161) (n=329) (n=165) 

Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a 

Mean change at 24 weeks 
± SD 

2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 

Adjusted treatment 
difference 

2.881 n/a 

p-value versus placebo <0.0011 0.0072 

ITT - LOCF population (n=287) (n=154) (n=289) (n=158) 

Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a 

Mean change at 24 weeks 
± SD 

2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 

Adjusted treatment 
difference 

3.541 n/a 

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p-value versus placebo <0.0011 <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 

ITT + RDO population (n=107) (n=60) (n=220) (n=101) 

Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 

Mean change at 24 weeks 
± SD 

1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 

Adjusted treatment 
difference 

4.271 2.091 

p-value versus placebo 0.0021 0.0151 

 Patients with moderate dementia 
(MMSE 10-17) 

Patients with mild dementia 
(MMSE 18-24) 

ITT + RDO population (n=87) (n=44) (n=237) (n=115) 

Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 

Mean change at 24 weeks 
± SD 

2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 

Adjusted treatment 
difference 

4.731 2.141 

p-value versus placebo 0.0021 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 
 
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. 
 
Metabolism 

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Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), 
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this 
metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro 
and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine 
metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg 
intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. 
 
Excretion  
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route 
of elimination. Following administration of 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. 
 
Elderly subjects  
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in 
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. 
 
Subjects with hepatic impairment  
The 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. 
 
Subjects with 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. 
 
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, 
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When 
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately 
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the 
maximum human dose, a multiple of approximately 6-fold was achieved in animals. 
 
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats 
and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Microcrystalline cellulose  
Hypromellose 
Colloidal silicon dioxide 
Magnesium stearate 

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Capsule shell 
Red iron oxide (E172) 
Yellow iron oxide (E 172) 
Titanium dioxide (E171) 
Gelatin 
Ink used for imprinting - Black S-1-17822/S-1-17823 
Shellac glaze-45%       
Iron oxide black   
Ammonium hydroxide     
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage instructions.  
 
6.5 Nature and contents of container 
 

- HDPE tablet container with a polypropylene cap and induction seal: 250 capsules 
- 28, 56 or 112 capsules in transparent PVC/Alu push through blisters  
- 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters 

 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/011 
EU/1/09/513/012 
EU/1/09/513/013 
EU/1/09/513/014 
EU/1/09/513/015 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17/04/2009 
 
 

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10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency  
http://www.ema.europa.eu  

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1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 6 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg 

For a full list of excipients, see section 6.1. 

 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule 
 
Orange cap imprinted with “R” & flesh color body imprinted with “6” 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Symptomatic treatment of mild to moderately severe Alzheimer’s dementia. 
Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’s 
disease. 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by a physician experienced in the diagnosis and 
treatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should 
be made according to current guidelines. Therapy with rivastigmine should only be started if a 
caregiver is available who will regularly monitor intake of the medicinal product by the patient. 
 
Rivastigmine should be administered twice a day, with morning and evening meals. The capsules 
should be swallowed whole.  
 
Initial dose:  
1.5 mg twice a day. 
 
Dose titration:  
The starting dose is 1.5 mg twice a day. If the dose is well tolerated after a minimum of two weeks of 
treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 
6mg 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 
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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 
Parkison’s disease patients with visual hallucinations (see section 5.1).  
 
Treatment effect has not been studied in placebo-controlled trials beyond 6 months. 
 
Re-initiation of therapy:  
If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily. 
Dose titration should then be carried out as described above. 
 
Renal and hepatic impairment:  
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 adverse reactions (see sections  4.4 and 5.2). 
 
Patients with severe hepatic impairment have not been studied (see section 4.4).  
 
Children:  
Rivastigmine is not recommended for use in children. 
 
4.3 Contraindications 
 
The use of this medicinal product is contraindicated in patients with 

- hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients 
used in the formulation. 

 
4.4 Special warnings and precautions for use 
 
The incidence and severity of adverse reactions generally increase with higher doses. If treatment is 
interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the 
possibility of adverse reactions (e.g. vomiting).  
 
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's 
dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia 
associated with Parkinson's disease) have been observed shortly after dose increase. They may respond 
to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).  
 
Gastrointestinal disorders such as nausea, 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.  
 

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In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as 
recommended in section 4.2 must be made. Some cases of severe vomiting were associated with 
oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments 
or high doses of rivastigmine.  
 
Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction 
defects (sino-atrial block, atrio-ventricular block) (see section 4.8).  
 
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients 
with active gastric or duodenal ulcers or patients predisposed to these conditions.  
 
Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or 
obstructive pulmonary disease.  
 
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended 
in treating patients predisposed to such diseases.  
 
The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with 
Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related 
cognitive decline) has not been investigated and therefore use in these patient populations is not 
recommended.  
 
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. 
Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or 
severity of tremor have been observed in patients with dementia associated with Parkinson's disease 
(see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. 
discontinuations due to tremor 1.7 % on rivastigmine vs 0 % on placebo). Clinical monitoring is 
recommended for these adverse reactions. 
 
Special Populations 
Patients with clinically significant renal or hepatic impairment might experience more adverse 
reactions (see sections 4.2 and 5.2). Patients with severe hepatic impairment have not been studied. 
However, Rivastigmine Teva 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, rivastigmine should not be given concomitantly with other 
cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.  
 
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam 
or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is 
not affected by administration of rivastigmine. No untoward effects on cardiac conduction were 
observed following concomitant administration of digoxin and rivastigmine.  
 
According to its metabolism, metabolic interactions with other medicinal products appear unlikely, 
although rivastigmine may inhibit the butyrylcholinesterase mediated metabolism of other substances.  
 
4.6 Fertility, pregnancy and lactation 
 

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For rivastigmine no clinical data on exposed pregnancies are available. No effects on fertility or 
embryofoetal development were observed in rats and rabbits, except at doses related to maternal 
toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine 
should not be used during pregnancy unless clearly necessary.  
 
In animals, rivastigmine is excreted into milk. It is not known if rivastigmine is excreted into human 
milk. Therefore, women on rivastigmine should not breast-feed 
 
4.7 Effects on ability to drive and use machines 
 
Alzheimer's disease may cause gradual impairment of driving performance or compromise the ability 
to use machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when 
initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate 
influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on 
rivastigmine to continue driving or operating complex machines should be routinely evaluated by the 
treating physician. 
 
4.8 Undesirable effects 
 
The most commonly reported adverse reactions are gastrointestinal, including nausea (38 %) and 
vomiting (23 %), especially during titration. Female patients in clinical studies were found to be more 
susceptible than male patients to gastrointestinal adverse reactions and weight loss.  
 
The following adverse reactions, listed below in Table 1, have been accumulated in patients with 
Alzheimer's dementia treated with rivastigmine.  
 
Adverse reactions in Table 1 are listed according to MedDRA system organ class and frequency 
category. Frequency categories are defined using the following convention: very common (≥1/10); 
common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare 
(<1/10,000); not known (cannot be estimated from the available data).  
 
Table 1  
 
Infections and infestations  

Very rare Urinary infection 

Metabolism and nutrition disorders  

Very common Anorexia 

Not known Dehydration 

Psychiatric disorders  

Common Agitation 

Common Confusion 

Common Anxiety 

Uncommon Insomnia 

Uncommon Depression 

Very rare Hallucinations 

Not known Aggression, restlessness 

Nervous system disorders  

Very common Dizziness 

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Common Headache 

Common Somnolence 

Common Tremor 

Uncommon Syncope 

Rare Seizures 

Very rare Extrapyramidal symptoms (including worsening of Parkinson's 
disease) 

Cardiac disorders  

Rare Angina pectoris 

Very rare Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, 
atrial fibrillation and tachycardia) 

Not known Sick sinus syndrome 

Vascular Disorders  

Very rare Hypertension 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Very common Diarrhoea 

Common Abdominal pain and dyspepsia 

Rare Gastric and duodenal ulcers 

Very rare Gastrointestinal haemorrhage 

Very rare Pancreatitis 

Not known Some cases of severe vomiting were associated with oesophageal 
rupture (see section 4.4). 

Hepatobiliary disorders  

Uncommon Elevated liver function tests 

Not known Hepatitis 

Skin and subcutaneous tissue disorders  

Common Hyperhydrosis 

Rare Rash 

Not known Pruritus 

General disorders and administration 
site conditions 

 

Common Fatigue and asthenia 

Common Malaise 

Uncommon Fall 

Investigations  

Common Weight loss 

 

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Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson’s 
disease treated with rivastigmine.  
 
Table 2 
 
Metabolism and nutrition disorders  

Common Anorexia 

Common Dehydration 

Psychiatric disorders  

Common Insomnia 

Common Anxiety 

Common Restlessness 

Not known Aggression 

Nervous system disorders  

Very common Tremor 

Common Dizziness 

Common Somnolence 

Common Headache 

Common Worsening of Parkinson’s disease 

Common Bradykinesia 

Common Dyskinesia 

Uncommon Dystonia 

Cardiac disorders  

Common Bradycardia 

Uncommon Atrial fibrillation 

Uncommon Atrioventricular block 

Not known Sick sinus syndrome 

Gastrointestinal disorders  

Very common Nausea 

Very common Vomiting 

Common Diarrhoea 

Common Abdominal pain and dyspesia 

Common Salivary hypersecretion 

Hepatobiliary disorders  

Not known Hepatitis 

Skin and subcutaneous tissue 
disorders 

 

Common Hyperhydrosis 

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Musculoskeletal and connective 
tissue disorders 

 

Common Muscle rigidity 

General disorders and 
administration site conditions 

 

Common Fatigue and asthenia 

Common Gait abnormality 

 
Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted 
with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined 
adverse events that may reflect worsening of parkinsonian symptoms.  
 
Table 3 
 
Pre-defined adverse events that may reflect 
worsening of parkinsonian symptoms in 
patients with dementia associated with 
Parkinson's disease 

Rivastigmine 
 
n (%) 

Placebo 
 
n (%) 

Total patients studied 362 (100) 179 (100) 

Total patients with pre-defined AE(s) 99 (27.3) 28 (15.6) 

Tremor 37 (10.2) 7 (3.9) 

Fall 21 (5.8) 11 (6.1) 

Parkinson’s disease (worsening) 12 (3.3) 2 (1.1) 

Salivary hypersecretion 5 (1.4) 0 

Dyskinesia 5 (1.4) 1 (0.6) 

Parkinsonism 8 (2.2) 1 (0.6) 

Hypokinesia 1 (0.3) 0 

Movement disorder 1 (0.3) 0 

Bradykinesia 9 (2.5) 3 (1.7) 

Dystonia 3 (0.8) 1 (0.6) 

Gait abnormality 5 (1.4) 0 

Muscle rigidity 1 (0.3) 0 

Balance disorder 3 (0.8) 2 (1.1) 

Musculoskeletal stiffness 3 (0.8) 0 

Rigors 1 (0.3) 0 

Motor dysfunction 1 (0.3) 0 

 
4.9 Overdose 
 
Symptoms 
Most cases of accidental overdose have not been associated with any clinical signs or symptoms and 
almost all of the patients concerned continued rivastigmine treatment. Where symptoms have 
occurred, they have included nausea, vomiting and diarrhoea, hypertension or hallucinations. Due to 
the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may 

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also occur. Ingestion of 46 mg occurred in one case; following conservative management the patient 
fully recovered within 24 hours. 
 
Treatment  
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition 
of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of 
rivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nausea 
and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse 
reactions should be given as necessary. 
 
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate 
is recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote 
is not recommended. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: anticholinesterases, ATC code: N06D A03 
 
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought to 
facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released by 
functionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect on 
cholinergic-mediated cognitive deficits in dementia associated with Alzheimer's disease and 
Parkinson's disease. 
  
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that 
temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases 
acetylcholinesterase (AChE) activity in CSF by approximately 40 % within the first 1.5 hours after 
administration. Activity of the enzyme returns to baseline levels about 9 hours after the maximum 
inhibitory effect has been achieved. In patients with Alzheimer's disease, inhibition of AChE in CSF 
by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibition 
of butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similar 
to that of AChE. 
 
Clinical studies in Alzheimer's dementia 
The efficacy of rivastigmine has been established through the use of three independent, domain 
specific, assessment tools which were assessed at periodic intervals during 6 month treatment periods. 
These include the ADAS-Cog (a performance based measure of cognition), the CIBIC-Plus (a 
comprehensive global assessment of the patient by the physician incorporating caregiver input), and 
the PDS (a caregiver-rated assessment of the activities of daily living including personal hygiene, 
feeding, dressing, household chores such as shopping, retention of ability to orient oneself to 
surroundings as well as involvement in activities relating to finances, etc.). 
 
The patients studied had an MMSE (Mini-Mental State Examination) score of 10 – 24. 
 
The results for clinically relevant responders pooled from two flexible dose studies out of the three 
pivotal 26-week multicentre studies in patients with mild-to-moderately severe Alzheimer's Dementia, 
are provided in Table 4 below. Clinically relevant improvement in these studies was defined a priori as 
at least 4-point improvement on the ADAS-Cog, improvement on the CIBIC-Plus, or at least a 10 % 
improvement on the PDS. 
 
In addition, a post-hoc definition of response is provided in the same table. The secondary definition 
of response required a 4-point or greater improvement on the ADAS-Cog, no worsening on the 
CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for responders in the 6 – 12 

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mg group, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in 
this indication vary and direct comparisons of results for different therapeutic agents are not valid. 
 
Table 4 
 
 Patients with Clinically Significant Response (%) 

 Intent to Treat Last Observation Carried 
Forward 

Response Measure Rivastigmine 
6–12 mg 
N=473 

Placebo 
N=472 

Rivastigmine 
6–12 mg 
N=379 

Placebo 
N=444 

ADAS-Cog: improvement of at 
least 4 points 

21*** 12 25*** 12 

CIBIC-Plus: improvement 29*** 18 32*** 19 

PDS: improvement of at least 
10% 

26*** 17 30*** 18 

At least 4 points improvement 
on ADAS-Cog with no 
worsening on CIBIC-Plus and 
PDS 

10* 6 12** 6 

*p<0.05, **p<0.01, ***p<0.001 
 
Clinical studies in dementia associated with Parkinson's disease 
The efficacy of rivastigmine in dementia associated with Parkinson's disease has been demonstrated in 
a 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-label 
extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score 
of 10 – 24. Efficacy has been established by the use of two independent scales which were assessed at 
regular intervals during a 6-month treatment period as shown in Table 5 below: the ADAS-Cog, a 
measure of cognition, and the global measure ADCS-CGIC (Alzheimer's Disease Cooperative Study-
Clinician's Global Impression of Change). 
 
Table 5 
 
Dementia associated 
with Parkinson's Disease 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADCS-CGIC 
Rivastigmine 

ADCS-CGIC 
Placebo 

ITT + RDO population (n=329) (n=161) (n=329) (n=165) 

Mean baseline ± SD 23.8±10.2 24.3±10.5 n/a n/a 

Mean change at 24 weeks 
± SD 

2.1±8.2 -0.7±7.5 3.8±1.4 4.3±1.5 

Adjusted treatment 
difference 

2.881 n/a 

p-value versus placebo <0.0011 0.0072 

ITT - LOCF population (n=287) (n=154) (n=289) (n=158) 

Mean baseline ± SD 24.0±10.3 24.5±10.6 n/a n/a 

Mean change at 24 weeks 
± SD 

2.5±8.4 -0.8±7.5 3.7±1.4 4.3±1.5 

Adjusted treatment 
difference 

3.541 n/a 

p-value versus placebo <0.0011 <0.0012 
1 Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a covariate. A 
positive change indicates improvement.  

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2 Mean data shown for convenience, categorical analysis performed using van Elteren test  
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs; LOCF: Last Observation Carried Forward 
 
Although a treatment effect was demonstrated in the overall study population, the data suggested that a 
larger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementia 
associated with Parkinson's disease. Similarly a larger treatment effect was observed in those patients 
with visual hallucinations (see Table 6). 
 
Table 6 
 
Dementia associated 
with Parkinson's Disease 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

ADAS-Cog 
Rivastigmine 

ADAS-Cog 
Placebo 

 Patients with visual 
hallucinations 

Patients without visual 
hallucinations 

ITT + RDO population (n=107) (n=60) (n=220) (n=101) 

Mean baseline ± SD 25.4±9.9 27.4±10.4 23.1±10.4 22.5±10.1 

Mean change at 24 weeks 
± SD 

1.0±9.2 -2.1±8.3 2.6±7.6 0.1±6.9 

Adjusted treatment 
difference 

4.271 2.091 

p-value versus placebo 0.0021 0.0151 

 Patients with moderate dementia 
(MMSE 10-17) 

Patients with mild dementia 
(MMSE 18-24) 

ITT + RDO population (n=87) (n=44) (n=237) (n=115) 

Mean baseline ± SD 32.6±10.4 33.7±10.3 20.6±7.9 20.7±7.9 

Mean change at 24 weeks 
± SD 

2.6±9.4 -1.8±7.2 1.9±7.7 -0.2±7.5 

Adjusted treatment 
difference 

4.731 2.141 

p-value versus placebo 0.0021 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 
 
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. 
 
Metabolism: 
Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour), 
primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, this 
metabolite shows minimal inhibition of acetylcholinesterase (<10 %). Based on evidence from in vitro 
and animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine 

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metabolism. Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg 
intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose. 
 
Excretion:  
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major route 
of elimination. Following administration of 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. 
 
Elderly subjects:  
While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in 
Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age. 
 
Subjects with hepatic impairment:  
The 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. 
 
Subjects with 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. 
 
No evidence of carcinogenicity was found in studies in mice and rats at the maximum tolerated dose, 
although the exposure to rivastigmine and its metabolites was lower than the human exposure. When 
normalised to body surface area, the exposure to rivastigmine and its metabolites was approximately 
equivalent to the maximum recommended human dose of 12 mg/day; however, when compared to the 
maximum human dose, a multiple of approximately 6-fold was achieved in animals. 
 
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats 
and rabbits gave no indication of teratogenic potential on the part of rivastigmine. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule contents 
Microcrystalline cellulose  
Hypromellose 
Colloidal silicon dioxide 
Magnesium stearate 
 
Capsule shell 
Red iron oxide (E172) 
Yellow iron oxide (E172) 

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Titanium dioxide (E171) 
Gelatin 
Ink used for imprinting - Black S-1-17822/S-1-17823 
Shellac glaze-45%       
Iron oxide black   
Ammonium hydroxide     
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
2 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage instructions.  
 
6.5 Nature and contents of container 
 

- HDPE tablet container with a polypropylene cap and induction seal: 250 capsules 
- 28, 56 or 112 capsules in transparent PVC/Alu push through blisters  
- 50 x 1 capsules in PVC/Alu push through perforated unit dose blisters 

 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/016 
EU/1/09/513/017 
EU/1/09/513/018 
EU/1/09/513/019 
EU/1/09/513/020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
17/04/2009 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this product is available on the website of the European Medicines Agency  
http://www.ema.europa.eu 

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ANNEX II 
 

A. MANUFACTURING AUTHORISATION HOLDERS 
RESPONSIBLE FOR BATCH RELEASE 

 
B. CONDITIONS OF THE MARKETING AUTHORISATION 

 

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A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH 
RELEASE 

 
Name and address of the manufacturers responsible for batch release 
 
Teva Pharmaceutical Works Private Limited Company . 
Pallagi út 13 
4042 Debrecen 
Hungary 
 
TEVA Pharmaceutical Works Private Limited Company 
H-2100 Gödöllő,  
Táncsics Mihály út 82 
Hungary  
 
TEVA UK Ltd  
Brampton Road,  
Hampden Park,  
Eastbourne,  
East Sussex,  
BN22 9AG  
United Kingdom 
 
Pharmachemie B.V.  
Swensweg 5,  
2031 GA Haarlem  
The Netherlands  
 
TEVA Santé, 
Rue Bellocier, 89100, 
Sens, 
France 
 
Teva Czech Industries s.r.o. 
Ostravska 29, c.p. 305 
747 70 Opava-Komarov 
Czech Republic 
 
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 OF THE MARKETING AUTHORISATION 
 
• CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON 

THE MARKETING AUTHORISATION HOLDER 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, Section 4.2 ). 
 
• CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable 
 

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• OTHER CONDITIONS 
 
Pharmacovigilance system 
 
The MAH must ensure that the system of pharmacovigilance presented in Module 1.8.1. of the 
Marketing Authorisation Application, is in place and functioning before and whilst the product is on 
the market. 
 
PSURs 
 
The PSUR submission schedule for Rivastigmine TEVA hard capsules should follow PSURs 
submission schedule for the reference medicinal product. 
 
 
 

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ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Carton – Rivastigmine Teva 1.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 1.5 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg   
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blisters 
28 hard capsules 
50 x 1 hard capsules 
56 hard capsules 
112 hard capsules 
 
Bottles 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
9. SPECIAL STORAGE CONDITIONS 
 
 

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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 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/001 
EU/1/09/513/002 
EU/1/09/513/003 
EU/1/09/513/004 
EU/1/09/513/005 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Rivastigmine Teva 1.5 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister – Rivastigmine Teva 1.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 1.5 mg hard capsules 
Rivastigmine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 
 
 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
Tablet container - Self-adhesive, paper label – Rivastigmine Teva 1.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 1.5 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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 

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Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/001 
EU/1/09/513/002 
EU/1/09/513/003 
EU/1/09/513/004 
EU/1/09/513/005 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Carton – Rivastigmine Teva 3 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 3 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blisters 
28 hard capsules 
50 x 1 hard capsules 
56 hard capsules 
112 hard capsules 
 
Bottles 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 

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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 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/006 
EU/1/09/513/007 
EU/1/09/513/008 
EU/1/09/513/009 
EU/1/09/513/010 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Rivastigmine Teva 3 mg 
 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister – Rivastigmine Teva 3 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 3 mg hard capsules 
Rivastigmine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 
 
Not applicable 
 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
Tablet container - Self-adhesive, paper label – Rivastigmine Teva 3 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 3 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 3 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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 

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Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/006 
EU/1/09/513/007 
EU/1/09/513/008 
EU/1/09/513/009 
EU/1/09/513/010 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Carton – Rivastigmine Teva 4.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 4.5 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blisters 
28 hard capsules 
50 x 1 hard capsules 
56 hard capsules 
112 hard capsules 
 
Bottles 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 

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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 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/011 
EU/1/09/513/012 
EU/1/09/513/013 
EU/1/09/513/014 
EU/1/09/513/015 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Rivastigmine Teva 4.5 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister – Rivastigmine Teva 4.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 4.5 mg hard capsules 
Rivastigmine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 
 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
Tablet Container - Self-adhesive, paper label – Rivastigmine Teva 4.5 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 4.5 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 4.5 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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 

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Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/011 
EU/1/09/513/012 
EU/1/09/513/013 
EU/1/09/513/014 
EU/1/09/513/015 
 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Carton – Rivastigmine Teva 6 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 6 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Blisters 
28 hard capsules 
50 x 1 hard capsules 
56 hard capsules 
112 hard capsules 
 
Bottles 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 

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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 
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/016 
EU/1/09/513/017 
EU/1/09/513/018 
EU/1/09/513/019 
EU/1/09/513/020 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Rivastigmine Teva 6 mg 

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister – Rivastigmine Teva 6 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 6 mg hard capsules 
Rivastigmine 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Teva Pharma B.V. 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
BN 
 
 
5. OTHER 
 
 

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PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING  
 
Tablet container - Self-adhesive, paper label – Rivastigmine Teva 6 mg hard capsules 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rivastigmine Teva 6 mg hard capsules 
Rivastigmine 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 6 mg  
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
250 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use.  
To be swallowed whole without crushing or opening 
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE REACH AND SIGHT OF CHILDREN 
 
Keep out of the reach and sight 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 

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Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/513/016 
EU/1/09/513/017 
EU/1/09/513/018 
EU/1/09/513/019 
EU/1/09/513/020 
 
 
13. BATCH NUMBER 
 
BN 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 

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B. PACKAGE LEAFLET 
 

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PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

 Rivastigmine Teva 1.5 mg hard capsules 
 Rivastigmine Teva 3 mg hard capsules 

 Rivastigmine Teva 4.5 mg hard capsules 
 Rivastigmine Teva 6 mg hard capsules  

Rivastigmine  
 

Read all of this leaflet carefully before you start taking this medicine. 
- 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. Do not pass it on to others. It may harm them, even 

if their symptoms are the same as yours. 
- If  any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, 

please tell your doctor or pharmacist. 
 
In this leaflet:  
1. What Rivastigmine Teva is and what it is used for 
2. Before you take Rivastigmine Teva 
3. How to take Rivastigmine Teva 
4. Possible side effects 
5. How to store Rivastigmine Teva 
6. Further information 
 
 
1. WHAT RIVASTIGMINE TEVA IS AND WHAT IT IS USED FOR 
 
The active substance of Rivastigmine Teva is rivastigmine 
 
Rivastigmine belongs to a class of substances called cholinesterase inhibitors.  
 
Rivastigmine Teva is used for the treatment of memory disorders in patients with Alzheimer’s disease. 
It is also used for the treatment of dementia in patients with Parkinson’s disease. 
 
 
2. BEFORE YOU TAKE RIVASTIGMINE TEVA 
 
 
Do NOT take Rivastigmine Teva 
 
- If you are allergic (hypersensitive) to rivastigmine (the active substance in Rivastigmine Teva) 

or to any of the other ingredients of Rivastigmine Teva listed in section 6 of this leaflet 
- If this applies to you, tell your doctor and do not take Rivastigmine Teva. 
 
Take special care with Rivastigmine Teva 
 
- if you have, or have ever had, irregular 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. 

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-  If you have gastrointestinal reactions such as feeling sick (nausea) and being sick (vomiting) and 
diarrhoea. You may become dehydrated (losing too much fluid) if vomiting or diarhoea 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 Rivastigmine Teva for several days, do not take the next dose until you have 
talked to your doctor. 
 
The use of Rivastigmine Teva in children and adolescents (age below 18 years) is not recommended.  
 
Taking other medicines 
 
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, 
including medicines obtained without a prescription. 
 
Rivastigmine Teva should not be given at the same time as other medicines with similar effects to 
Rivastigmine Teva. Rivastigmine Teva might interfere with anticholinergic medicines (medicines used 
to relieve stomach cramps or spasms, to treat Parkinson’s disease or to prevent travel sickness). 
 
If you have to undergo surgery whilst taking Rivastigmine Teva, tell your doctor before you are given 
any anaesthetics, because Rivastigmine Teva may exaggerate the effects of some muscle relaxants 
during anaesthesia. 
 
Pregnancy and breast-feeding 
Tell your doctor if you become pregnant during treatment. It is preferable to avoid the use of 
Rivastigmine Teva during pregnancy, unless clearly necessary.  
 
You should not breast-feed during treatment with Rivastigmine Teva.  
 
Ask your doctor or pharmacist for advice before taking any medicine.  
 
Driving and using machines 
Your doctor will tell you whether your illness allows you to drive vehicles and use machines safely.. 
Rivastigmine Teva may cause dizziness and somnolence, mainly at the start of treatment or when 
increasing 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 RIVASTIGMINE TEVA 
 
Always take Rivastigmine Teva exactly as your doctor has told you. You should check with your 
doctor or pharmacist if you are not sure. 
 
How to start treatment 
Your doctor will tell you what dose of Rivastigmine Teva to take. 
• Treatment usually starts with a low dose. 
• Your doctor will slowly increase your dose depending on how you respond to the 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 Rivastigmine Teva for several days, do not take the next dose until you have 
talked to your doctor. 
 

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Taking this medicine 
• Tell your caregiver that you are taking Rivastigmine Teva. 
• To benefit from your medicine, take it every day. 
• Take Rivastigmine Teva 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 Rivastigmine Teva than you should 
If you accidentally take more Rivastigmine Teva than you should, inform your doctor. You may 
require medical attention. Some people who have accidentally taken too much Rivastigmine Teva 
have experienced  feeling sick (nausea), being sick (vomiting), diarrhoea, high blood pressure and 
hallucinations. Slow heart beat and fainting may also occur.  
 
If you forget to take Rivastigmine Teva 
If you find you have forgotten to take your dose of Rivastigmine Teva, wait and take the next dose at 
the usual time. Do not take a double dose to make up for a forgotten dose. 
 
 
4. POSSIBLE SIDE EFFECTS 
 
Like all medicines, Rivastigmine Teva 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 slowly go away as your body gets used to the medicine. 
 
The frequencies are defined as: 
Very common (affects more than 1 patient in 10) 
Common (affects 1 to 10 patients in 100) 
Uncommon (affects 1 to 10 patients in 1,000) 
Rare (affects 1 to 10 patients in 10, 000) 
Very rare (affects less than 1 patient in 10,000) 
Not known (frequency cannot be estimated from the available data) 
 
Very common  
• Feeling dizzy 
• Loss of appetite 
• Stomach problems such as feeling sick (nausea) or being sick (vomiting), diarrhoea 
 
Common 
• Anxiety 
• Sweating 
• Headache 
• Heartburn 
• Weight loss 
• Stomach pain  
•  Feeling agitated 
• Feeling tired or weak 
• Generally feeling unwell 
• Trembling or feeling confused 
 
Uncommon 
• Depression 
• Difficulty in sleeping 
• Fainting or accidentally falling 
• Changes in how your liver is working  
 

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Rare 
• Chest pain 
• Rash, itching 
 Fits (seizures)  
• Ulcers in your stomach or intestine 
 
Very rare 
• 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   
• 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 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 
• Trembling  
 
Common 
• Anxiety 
• Feeling restless, 
• Slow 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 
 
Uncommon 
• Uneven heartbeat and poor control of movements 

 
Other side effects seen with Rivastigmine transdermal patches and which may occur with hard 
capsules: 
 
Common 
• Fever 
• Severe confusion 
 
If you get any of these side effects, contact your doctor as you may need medical assistance. 
 
If any of these side effects get serious, or if you notice any side effects not listed in this leaflet, please 
tell your doctor or pharmacist. 
 

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5. HOW TO STORE RIVASTIGMINE TEVA 
 
Keep out of the reach and sight of children. 
 
Do not use Rivastigmine Teva after the expiry date that is stated on the carton. The expiry date refers 
to the last day of that month. 
 
This medicinal product does not require any special storage conditions 
 
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment. 
 
 
6. FURTHER INFORMATION 
 
What Rivastigmine Teva contains 
 
The active substance is rivastigmine  
Rivastigmine Teva 1.5 mg hard capsules contains 1.5 mg rivastigmine as rivastigmine hydrogen 
tartrate 
Rivastigmine Teva 3 mg hard capsules contains 3 mg rivastigmine as  rivastigmine hydrogen tartrate 
Rivastigmine Teva 4.5 mg hard capsules contains 4.5 mg rivastigmine as  rivastigmine hydrogen 
tartrate 
Rivastigmine Teva 6 mg hard capsules contains 6 mg rivastigmine as  rivastigmine hydrogen tartrate 
 
The other ingredients are:  
Capsule contents - microcrystalline cellulose, hypromellose, colloidal silicon dioxide, magnesium 
stearate.   
Capsule shell – titanium dioxide (E171), gelatin and ink used for imprinting Black S-1-17822/S-1-
17823 (shellac glaze-45% in ethanol containing iron oxide black, N-butyl alcohol, isopropyl alcohol, 
propylene alcohol and ammonium hydroxide).  In addition, Rivastigmine Teva 3 mg, 4.5 mg and 6 mg 
hard capsules contain red iron oxide (E172) and yellow iron oxide (E 172). 
 
What Rivastigmine Teva looks like and contents of the pack 
 
Hard capsule 
 
- Rivastigmine Teva 1.5 mg hard capsules: White cap imprinted with “R” & white body 

imprinted with “1.5” 
- Rivastigmine Teva 3 mg hard capsules: Flesh colour cap imprinted with “R” & flesh colour 

body imprinted with “3” 
- Rivastigmine Teva 4.5 mg hard capsules: Orange colour cap imprinted with “R” & orange 

colour body imprinted with “4.5” 
- Rivastigmine Teva 6 mg hard capsules: Orange cap imprinted with “R” & flesh colour body 

imprinted with “6” 
 
Rivastigmine Teva hard capsules are available in blister packs of 28, 56 and 112 capsules,  perforated 
blisters containing 50 x 1 capsules, and bottles containing 250 capsules. 
 
Marketing Authorisation Holder  
 
Teva Pharma B.V. 
Computerweg 10, 3542 DR Utrecht 
The Netherlands 
 
Manufacturer 

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TEVA Pharmaceutical Works Private Limited Company  
Pallagi út 13,  
4042 Debrecen, 
Hungary 
 
Or: 
TEVA Pharmaceutical Works Private Limited Company 
H-2100 Gödöllő,  
Táncsics Mihály út 82 
Hungary  
 
Or: 
TEVA UK Ltd  
Brampton Road,  
Hampden Park,  
Eastbourne,  
East Sussex,  
BN22 9AG  
United Kingdom 
 
Or: 
Pharmachemie B.V.  
Swensweg 5,  
2031 GA Haarlem  
The Netherlands   
 
Or: 
TEVA Santé, 
Rue Bellocier, 89100, 
Sens, 
France 
 
Or:Teva Czech Industries s.r.o. 
Ostravska 29, c.p. 305 
747 70 Opava-Komarov 
Czech Republic 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 

België/Belgique/Belgien  
Teva Pharma Belgium N.V./S.A./AG  
Tel/Tél: +32 3 820 73 73  

Luxembourg/Luxemburg  
Teva Pharma Belgium S.A.  
Tél/Tel: +32 3 820 73 73 
  

България  
Тева Фармасютикълс България ЕООД 
Teл: +359 2 489 95 82  

Magyarország  
Teva Magyarország Zrt  
Tel.: +36 1 288 64 00  

Česká republika  
Teva Pharmaceuticals CR, s.r.o.  
Tel: +420 251 007 111  

Malta  
Drugsales Ltd 
Tel: +356 21 419 070/1/2 

Danmark  
Teva Denmark A/S  
Tlf: +45 44 98 55 11  

Nederland  
Teva Nederland B.V. 
Tel: +31 (0) 800 0228400  

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Deutschland 
Teva GmbH 
Tel: + 49 731 402 08 

Norge 
Teva Norway AS 
Tlf: +46 66 77 55 90 

Eesti 
Teva Eesti esindus UAB Sicor Biotech Eesti 
filiaal 
Tel: +372 6610801 

Österreich 
ratiopharm Arzneimittel Vertriebs-GmbH 
Tel: +43 1 97 007 

Ελλάδα 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

Polska 
Teva Pharmaceuticals Polska Sp. z o.o. 
Tel.: +(48) 22 345 93 00 

España 
Teva Pharma, S.L.U 
Tél: +(34) 91 387 32 80   

Portugal 
Teva Pharma - Produtos Farmacêuticos Lda 
Tel: (351) 214 235 910 

France 
Teva Santé 
Tél: +(33) 1 55 91 7800 

România 
Teva Pharmaceuticals S.R.L 
Tel: +4021 230 65 24 

Ireland 
Teva Pharmaceuticals Ireland 
Tel: +353 (0)42 9395 892 

Slovenija 
Pliva Ljubljana d.o.o. 
Tel: +386 1 58 90 390 

Ísland 
Teva UK Limited 
Sími: +(44) 1323 501 111. 

Slovenská republika 
Teva Pharmaceuticals Slovakia s.r.o. 
Tel: +(421) 2 5726 7911 

Italia 
Teva Italia S.r.l. 
Tel: +(39) 0289179805 

Suomi/Finland 
ratiopharm Oy 
Puh/Tel: +(46) 42 12 11 00 

Κύπρος 
Teva Ελλάς Α.Ε. 
Τηλ: +30 210 72 79 099 

Sverige 
Teva Sweden AB 
Tel: +(46) 42 12 11 00 

Latvija 
UAB Sicor Biotech filiāle Latvijā  
Tel: +371 67 784 980 

United Kingdom 
Teva UK Limited 
Tel: +(44) 1323 501 111 

Lietuva 
UAB “Sicor Biotech” 
Tel: +370 5 266 02 03 

 

 
 
This leaflet was last approved in {MM/YYYY}. 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
  
 
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http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OF THE MARKETING AUTHORISATION
	A. LABELLING
	B. PACKAGE LEAFLET