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RIVASTIGMINE 4.5 MG CAPSULES HARD

Active substance(s): RIVASTIGMINE HYDROGEN TARTRATE / RIVASTIGMINE HYDROGEN TARTRATE / RIVASTIGMINE HYDROGEN TARTRATE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Rivastigmine 4.5 mg capsules, hard

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains rivastigmine hydrogen tartrate corresponding to
rivastigmine 4.5 mg.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Capsules, hard
Rivastigmine 4.5 mg hard capsules, are caramel/caramel hard gelatine capsule
imprinted with “RIVA 4.5mg” on body with black ink containing white to offwhite granular powder of 4.5 mg of rivastigmine.

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 drug intake by the patient.
Posology
Rivastigmine capsules should be administered twice a day, with morning and evening
meals. The capsules should be swallowed whole.
Initial dose
1.5 mg twice a day.
Dose titration
The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum
of two weeks of treatment, the dose may be increased to 3 mg twice a day.
Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on
good tolerability of the current dose and may be considered after a minimum of two
weeks of treatment at that dose level.
If adverse effects (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 effects persist, the daily dose
should be temporarily reduced to the previous well-tolerated dose or the treatment
may be discontinued.
Maintenance dose
The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit
patients should be maintained on their highest well tolerated dose. The recommended
maximum daily dose is 6 mg twice a day.
Maintenance treatment can be continued for as long as a therapeutic benefit for the
patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a
regular basis, especially for patients treated at doses less than 3 mg twice a day. If
after 3 months of maintenance dose treatment the patient’s rate of decline in dementia
symptoms is not altered favourably, the treatment should be discontinued.
Discontinuation should also be considered when evidence of a therapeutic effect is no
longer present.
Individual response to rivastigmine cannot be predicted. However, a greater treatment
effect was seen in Parkinson’s disease patients with moderate dementia. Similarly a
larger effect was observed in Parkinson’s disease patients with visual hallucinations
(see section 5.1).
Treatment effect has not been studied in placebo-controlled trials beyond 6 months.

Re-initiation of therapy
If treatment is interrupted for more than three days, it should be re-initiated at 1.5 mg
twice daily. Dose titration should then be carried out as described above.
Renal and hepatic impairment
No dose adjustment is necessary for patients with mild to moderate renal or hepatic
impairment.
However, due to increased exposure in these populations dosing recommendations to
titrate according to individual tolerability should be closely followed as patients with
clinically significant renal or hepatic impairment might experience more dosedependent adverse reactions. Patients with severe hepatic impairment have not been
studied (see sections 4.4 and 5.2), however, rivastigmine capsules may be used in this
patient population provided close monitoring is exercised (see sections 4.4 and 5.2).
Paediatric population
There is no relevant use of rivastigmine in the paediatric population in the treatment
of Alzheimer’s disease.
4.3

Contraindications

The use of this medicinal product is contraindicated in patients with known hypersensitivity
to the active substance rivastigmine, to other carbamate derivatives or to any of the excipients
listed in section 6.1.
Previous history of application site reactions suggestive of allergic contact dermatitis with
rivastigmine patch (see section 4.4).

4.4

Special warnings and precautions for use

The incidence and severity of adverse reactions generally increase with higher doses.
If treatment is interrupted for more than three days, it should be re-initiated at 1.5 mg
twice daily to reduce the possibility of adverse reactions (e.g. vomiting).
Skin application site reactions may occur with rivastigmine patch and are usually mild
or moderate in intensity. These reactions are not in themselves an indication of
sensitisation. However, use of rivastigmine patch may lead to allergic contact
dermatitis.
Allergic contact dermatitis should be suspected if application site reactions spread
beyond the patch size, if there is evidence of a more intense local reaction (e.g.
increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly
improve within 48 hours after patch removal. In these cases, treatment should be
discontinued (see section 4.3).
Patients who develop application site reactions suggestive of allergic contact
dermatitis to rivastigmine patch and who still require rivastigmine treatment should
only be switched to oral rivastigmine after negative allergy testing and under close
medical supervision. It is possible that some patients sensitised to rivastigmine by
exposure to rivastigmine patch may not be able to take rivastigmine in any form.
There have been rare post-marketing reports of patients experiencing allergic
dermatitis (disseminated) when administered rivastigmine irrespective of the route of

administration (oral, transdermal). In these cases, treatment should be discontinued
(see section 4.3).
Patients and caregivers should be instructed accordingly.
Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with
Alzheimer’s dementia and worsening of extrapyramidal symptoms, in particular
tremor, in patients with dementia associated with Parkinson’s disease) have been
observed shortly after dose increase. They may respond to a dose reduction. In other
cases, Rivastigmine capsules have been discontinued (see section 4.8).
Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related,
and may occur particularly when initiating treatment and/or increasing the dose (see
section 4.8). These adverse reactions occur more commonly in women. Patients who
show signs or symptoms of dehydration resulting from prolonged vomiting or
diarrhoea can be managed with intravenous fluids and dose reduction or
discontinuation if recognised and treated promptly. Dehydration can be associated
with serious outcomes.
Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors,
including rivastigmine, have been associated with weight loss in these patients.
During therapy patient’s weight should be monitored.
In case of severe vomiting associated with rivastigmine treatment, appropriate dose
adjustments as recommended in section 4.2 must be made. Some cases of severe
vomiting were associated with oesophageal rupture (see section 4.8). Such events
appeared to occur particularly after dose increments or high doses of rivastigmine.
Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence
of torsade de pointes, predominantly in patients with risk factors. Caution is advised
in patients at higher risk of developing torsade de pointes; for example, those with
uncompensated heart failure, recent myocardial infarction, bradyarrhythmias, a
predisposition to hypokalaemia or hypomagnesaemia, or concomitant use with
medicinal products known to induce QT prolongation and/or torsade de pointes (see
sections 4.5 and 4.8).
Care must be taken when using rivastigmine in patients with sick sinus syndrome or
conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).
Rivastigmine may cause increased gastric acid secretions. Care should be exercised in
treating patients with active gastric or duodenal ulcers or patients predisposed to these
conditions.
Cholinesterase inhibitors should be prescribed with care to patients with a history of
asthma or obstructive pulmonary disease.
Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution
is recommended in treating patients predisposed to such diseases.

The use of rivastigmine in patients with severe dementia of Alzheimer’s disease or
associated with Parkinson’s disease, other types of dementia or other types of memory
impairment (e.g. age-related cognitive decline) has not been investigated and
therefore use in these patient populations is not recommended.
Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal
symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an
increased incidence or severity of tremor have been observed in patients with
dementia associated with Parkinson’s disease (see section 4.8). These events led to the
discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor
1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for
these adverse reactions.
Special populations
Patients with clinically significant renal or hepatic impairment might experience more
adverse reactions (see sections 4.2 and 5.2). Dosing recommendations to titrate
according to individual tolerability must be closely followed. Patients with severe
hepatic impairment have not been studied. However, Rivastigmine capsules may be
used in this patient population and close monitoring is necessary.
Patients with body weight below 50 kg may experience more adverse reactions and
may be more likely to discontinue due to adverse reactions.
4.5
Interaction with other medicinal products and other forms of interaction
As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type
muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic
agents. Possible dose adjustments or temporarily stopping treatment can be considered if
needed.
In view of its pharmacodynamic effects and possible additive effects, rivastigmine should not
be given concomitantly with other cholinomimetic substances. Rivastigmine might interfere
with the activity of anticholinergic medicinal products (e.g. oxybutinin, tolterodine).
Additive effects leading to bradycardia (which may result in syncope) have been reported
with the combined use of various beta-blockers (including atenolol) and rivastigmine.
Cardiovascular beta-blockers are expected to be associated with the greatest risk, but reports
have also been received in patients using other beta-blockers. Therefore, caution should be
exercised when rivastigmine is combined with beta-blockers and also other bradycardia
agents (e.g. class III antiarrhythmic agents, calcium channel antagonists, digitalis glycoside,
pilocarpin).
Since bradycardia constitutes a risk factor in the occurrence of torsades de pointes, the
combination of rivastigmine with torsades de pointes-inducing medicinal products such as
antipsychotics i.e. some phenothiazines (chlorpromazine, levomepromazine), benzamides
(sulpiride, sultopride, amisulpride, tiapride, veralipride), pimozide, haloperidol, droperidol,
cisapride, citalopram, diphemanil, erythromycin IV, halofantrin, mizolastin, methadone,
pentamidine and moxifloxacine should be observed with caution and clinical monitoring
(ECG) may also be required.
No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin,
diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time
induced by warfarin is not affected by administration of rivastigmine. No untoward effects on
cardiac conduction were observed following concomitant administration of digoxin and
rivastigmine.

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

4.6

Fertility, pregnancy and lactation

Pregnancy
In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if
this occurs in humans. No clinical data on exposed pregnancies are available. In peri/postnatal
studies in rats, an increased gestation time was observed.
Rivastigmine should not be used during pregnancy unless clearly necessary.
Breastfeeding
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.
Fertility
No adverse effects of rivastigmine were observed on fertility or reproductive performance in
rats (see section 5.3). Effects of rivastigmine on human fertility are not known.

4.7

Effects on ability to drive and use machines
Alzheimer’s disease may cause gradual impairment of driving performance or
compromise the ability to use machinery. Furthermore, rivastigmine can
induce dizziness and somnolence, mainly when initiating treatment or
increasing the dose. As a consequence, rivastigmine has minor or moderate
influence on the ability to drive and use machines. Therefore, the ability of
patients with dementia on rivastigmine to continue driving or operating
complex machines should be routinely evaluated by the treating physician.

4.8

Undesirable effects

Summary of the safety profile
The most commonly reported adverse drug reactions (ADRs) are gastrointestinal,
including nausea (38%) and vomiting (23%), especially during titration. Female
patients in clinical studies were found to be more susceptible than male patients to
gastrointestinal adverse reactions and weight loss.
Tabulated list of adverse reactions
Adverse reactions in Table 1 and Table 2 are listed according to MedDRA system
organ class and frequency category. Frequency categories are defined using the
following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon
(≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known
(cannot be estimated from the available data).
The following adverse drug reactions, listed below in Table 1, have been accumulated
in patients with Alzheimer’s dementia treated with Rivastigmine capsules.

Table 1
Infections and infestations
Very rare

Urinary infection

Metabolism and nutrition disorders
Very common
Common
Not known

Anorexia
Decreased appetite
Dehydration

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

Nightmares
Agitation
Confusion
Anxiety
Insomnia
Depression
Hallucinations
Aggression, restlessness

Nervous system disorders
Very common
Common
Common
Common
Uncommon
Rare
Very rare

Dizziness
Headache
Somnolence
Tremor
Syncope
Seizures
Extrapyramidal symptoms (including worsening of
Parkinson's disease)

Cardiac disorders
Rare
Very rare
Not known

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

Vascular disorders
Very rare

Hypertension

Gastrointestinal disorders
Very common
Very common
Very common
Common
Rare
Very rare
Very rare
Not known

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Gastric and duodenal ulcers
Gastrointestinal haemorrhage
Pancreatitis
Some cases of severe vomiting were associated

with oesophageal rupture (see section 4.4).
Hepato-biliary disorders
Uncommon
Not known

Elevated liver function tests
Hepatitis

Skin and subcutaneous tissue disorders
Common
Rare
Not known

Hyperhydrosis
Rash
Pruritus, allergic dermatitis (disseminated)

General disorders and administration site conditions
Common
Common
Uncommon

Fatigue and asthenia
Malaise
Fall

Investigations
Common
Weight loss
The following additional adverse reactions have been observed with rivastigmine
transdermal patches: delirium, pyrexia, decreased appetite, urinary incontinence
(common), psychomotor hyperactivity (uncommon), erythema, urticaria, vesicles,
allergic dermatitis (not known).
Table 2 shows the adverse reactions reported during clinical studies conducted in
patients with dementia associated with Parkinson’s disease treated with Rivastigmine
capsules.
Table 2
Metabolism and nutrition disorders
Common
Common

Decreased appetite
Dehydration

Psychiatric disorders
Common
Common
Common
Common
Common
Not known

Insomnia
Anxiety
Restlessness
Hallucination, visual
Depression
Aggression

Nervous system disorders
Very common
Common
Common
Common
Common
Common
Common

Tremor
Dizziness
Somnolence
Headache
Worsening of Parkinson's disease
Bradykinesia
Dyskinesia

Common
Common
Uncommon

Hypokinesia
Cogwheel rigidity
Dystonia

Cardiac disorders
Common
Uncommon
Uncommon
Not known

Bradycardia
Atrial Fibrillation
Atrioventricular block
Sick sinus syndrome

Vascular disorders
Common
Uncommon

Hypertension
Hypotension

Gastrointestinal disorders
Very common
Very common
Common
Common
Common

Nausea
Vomiting
Diarrhoea
Abdominal pain and dyspepsia
Salivary hypersecretion

Hepatobiliary disorders
Not known

Hepatitis

Skin and subcutaneous tissue disorders
Common
Not known

Hyperhydrosis
Allergic dermatitis (disseminated)

General disorders and administration site conditions
Very common
Common
Common
Common

Fall
Fatigue and asthenia
Gait disturbance
Parkinson gait

The following additional adverse reaction has been observed in a study of patients
with dementia associated with Parkinson’s disease treated with rivastigmine
transdermal patches: agitation (common).
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
Total patients studied
Total patients with pre-defined AE(s)

rivastigmine
n (%)

Placebo
n (%)

362 (100)
99 (27.3)

179 (100)
28 (15.6)

Tremor
Fall
Parkinson’s disease (worsening)
Salivary hypersecretion
Dyskinesia
Parkinsonism
Hypokinesia
Movement disorder
Bradykinesia
Dystonia
Gait abnormality
Muscle rigidity
Balance disorder
Musculoskeletal stiffness
Rigors
Motor dysfunction

37 (10.2)
21 (5.8)
12 (3.3)
5 (1.4)
5 (1.4)
8 (2.2)
1 (0.3)
1 (0.3)
9 (2.5)
3 (0.8)
5 (1.4)
1 (0.3)
3 (0.8)
3 (0.8)
1 (0.3)
1 (0.3)

7 (3.9)
11 (6.1)
2 (1.1)
0
1 (0.6)
1 (0.6)
0
0
3 (1.7)
1 (0.6)
0
0
2 (1.1)
0
0
0

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9

Overdose

Symptoms
Most cases of accidental overdose have not been associated with any clinical signs or
symptoms and almost all of the patients concerned continued rivastigmine treatment 24 hours
after the overdose.
Cholinergic toxicity has been reported with muscarinic symptoms that are observed with
moderate poisonings such as miosis, flushing, digestive disorders including abdominal pain,
nausea, vomiting and diarrhoea, bradycardia, bronchospasm and increased bronchial
secretions, hyperhidrosis, involuntary urination and/or defecation, lacrimation, hypotension
and salivary hypersecretion.
In more severe cases nicotinic effects might develop such as muscular weakness,
fasciculations, seizures and respiratory arrest with possible fatal outcome.
Additionally there have been post-marketing cases of dizziness, tremor, headache,
somnolence, confusional state, hypertension, hallucinations and malaise.
Management
As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase
inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no
further dose of rivastigmine should be administered for the next 24 hours. In overdose
accompanied by severe nausea and vomiting, the use of antiemetics should be considered.
Symptomatic treatment for other adverse events should be given as necessary.
In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine
sulphate is recommended, with subsequent doses based on clinical response. Use of
scopolamine as an antidote is not recommended.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: psychoanaleptics, anticholinesterases, ATC code: N06DA03
Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought
to facilitate cholinergic neurotransmission by slowing the degradation of acetylcholine
released by functionally intact cholinergic neurones. Thus, rivastigmine may have an
ameliorative effect on cholinergic-mediated cognitive deficits in dementia associated with
Alzheimer’s disease and Parkinson’s disease.
Rivastigmine interacts with its target enzymes by forming a covalently bound complex that
temporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreases
acetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours
after administration. Activity of the enzyme returns to baseline levels about 9 hours after the
maximum inhibitory effect has been achieved. In patients with Alzheimer’s disease, inhibition
of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the
highest dose tested. Inhibition of butyrylcholinesterase activity in CSF of 14 Alzheimer
patients treated by rivastigmine was similar to that of AChE.
Clinical studies in Alzheimer’s dementia
The efficacy of rivastigmine has been established through the use of three independent,
domain specific, assessment tools which were assessed at periodic intervals during 6 month
treatment periods. These include the ADAS-Cog (Alzheimer’s Disease Assessment Scale –
Cognitive Subscale, a performance based measure of cognition), the CIBIC-Plus (Clinician’s
Interview Based Impression of Change-Plus, a comprehensive global assessment of the
patient by the physician incorporating caregiver input), and the PDS (Progressive
Deterioration Scale, a caregiver-rated assessment of the activities of daily living including
personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to
orient oneself to surroundings as well as involvement in activities relating to finances, etc.).
The patients studied had an MMSE (Mini-Mental State Examination) score of 10–24.
The results for clinically relevant responders pooled from two flexible dose studies out of the
three pivotal 26-week multicentre studies in patients with mild-to-moderately severe
Alzheimer’s Dementia, are provided in Table 4 below. Clinically relevant improvement in
these studies was defined a priori as at least 4-point improvement on the ADAS-Cog,
improvement on the CIBIC-Plus, or at least a 10% improvement on the PDS.
In addition, a post-hoc definition of response is provided in the same table. The secondary
definition of response required a 4-point or greater improvement on the ADAS-Cog, no
worsening on the CIBIC-Plus, and no worsening on the PDS. The mean actual daily dose for
responders in the 6–12 mg group, corresponding to this definition, was 9.3 mg. It is important
to note that the scales used in this indication vary and direct comparisons of results for
different therapeutic agents are not valid.
Table 4
Patients with Clinically Significant Response (%)
Intent to Treat
Last Observation Carried
Forward

Response Measure

ADAS-Cog: improvement of at least 4
points
CIBIC-Plus: improvement
PDS: improvement of at least 10%

Rivastigmine
6–12 mg
N=473
21***

Placebo
N=472

Placebo
N=444

12

Rivastigmine
6–12 mg
N=379
25***

29***
26***

18
17

32***
30***

19
18

10*

6

12**

6

At least 4 points improvement on
ADAS-Cog with no worsening on
CIBIC-Plus and PDS
*p<0.05, **p<0.01, ***p<0.001

12

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 24week multicentre, double-blind, placebo-controlled core study and its 24week 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 6month 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
ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks ± SD
Adjusted treatment difference
p-value versus placebo
ITT - LOCF population

ADAS-Cog
Rivastigmine
(n=329)

ADAS-Cog
Placebo
(n=161)

ADCSCGIC ADCS-CGIC
Rivastigmine Placebo
(n=329)
(n=165)

23.8 ± 10.2
2.1 ± 8.2

24.3 ± 10.5
-0.7 ± 7.5

n/a
3.8 ± 1.4

2.881
<0.0011
(n=287)

n/a
4.3 ± 1.5
n/a
0.0072

(n=154)

(n=289)

(n=158)

24.0 ± 10.3
24.5 ± 10.6
n/a
n/a
Mean baseline ± SD
2.5
±
8.4
-0.8
±
7.5
3.7
±
1.4
4.3 ± 1.5
Mean change at 24 weeks ± SD
1
Adjusted treatment difference
n/a
3.54
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
ADAS-Cog
Rivastigmine
Placebo
Patients with visual

ADAS-Cog
ADAS-Cog
Rivastigmine
Placebo
Patients without visual hallucinations

ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks
± SD
Adjusted treatment
difference
p-value versus placebo

ITT + RDO population
Mean baseline ± SD
Mean change at 24 weeks
± SD

hallucinations
(n=107)

(n=60)

(n=220)

(n=101)

25.4 ± 9.9
1.0 ± 9.2

27.4 ± 10.4
-2.1 ± 8.3

23.1 ± 10.4
2.6 ± 7.6

22.5 ± 10.1
0.1 ± 6.9

4.271
0.0021
Patients with moderate
dementia (MMSE 10-17)
(n=87)
(n=44)

2.091
0.0151
Patients with mild dementia (MMSE
18-24)
(n=237)
(n=115)

32.6 ± 10.4
2.6 ± 9.4

20.6 ± 7.9
1.9 ± 7.7

33.7 ± 10.3
-1.8 ± 7.2

20.7 ± 7.9
-0.2 ± 7.5

Adjusted treatment
difference
2.141
4.731
1
p-value versus placebo
0.002
0.0101
1
Based on ANCOVA with treatment and country as factors and baseline ADAS-Cog as a
covariate. A positive change indicates improvement.
ITT: Intent-To-Treat; RDO: Retrieved Drop Outs
The European Medicines Agency has waived the obligation to submit the results of studies
with rivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s
dementia and in the treatment of dementia in patients with idiopathic Parkinson’s disease (see
section 4.2 for information on paediatric use).

5.2
Pharmacokinetic properties
Absorption
Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are
reached in approximately 1 hour. As a consequence of the drug’s interaction with its
target enzyme, the increase in bioavailability is about 1.5-fold greater than that
expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about
36% ±13%. Administration of rivastigmine with food delays absorption (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.
Biotransformation
Rivastigmine is rapidly and extensively metabolised (half-life in plasma
approximately 1 hour), primarily via cholinesterase-mediated hydrolysis to the
decarbamylated metabolite. In vitro, this metabolite shows minimal inhibition of
acetylcholinesterase (<10%). Based on in vitro studies, no pharmacokinetic
interaction is expected with medicinal products metabolised by the following
cytochromes isoenzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9,
CYP2C8, CYP2C19, or CYP2B6. Based on evidence from animal studies the major

cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism.
Total plasma clearance of rivastigmine was approximately 130 l/h after a 0.2 mg
intravenous dose and decreased to 70 l/h after a 2.7 mg intravenous dose.
Elimination
Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is
the major route of elimination. Following administration of 14C-rivastigmine, renal
elimination was rapid and essentially complete (>90%) within 24 hours. Less than 1%
of the administered dose is excreted in the faeces. There is no accumulation of
rivastigmine or the decarbamylated metabolite in patients with Alzheimer’s disease.
A population pharmacokinetic analysis showed that nicotine use increases the oral
clearance of rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers
and 549 non-smokers) following rivastigmine oral capsule doses up to 12 mg/day.
Older people: While bioavailability of rivastigmine is greater in elderly than in young
healthy volunteers, studies in Alzheimer patients aged between 50 and 92 years
showed no change in bioavailability with age.
Hepatic impairment: The Cmax of rivastigmine was approximately 60% higher and the
AUC of rivastigmine was more than twice as high in subjects with mild to moderate
hepatic impairment than in healthy subjects.
Renal impairment: Cmax and AUC of rivastigmine were more than twice as high in
subjects with moderate renal impairment compared with healthy subjects; however
there were no changes in Cmax and AUC of rivastigmine in subjects with severe renal
impairment.
5.3

Preclinical safety data

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated
with an exaggerated pharmacological action. No target organ toxicity was observed.
No safety margins to human exposure were achieved in the animal studies due to the
sensitivity of the animal models used.
Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests,
except in a chromosomal aberration test in human peripheral lymphocytes at a dose
104 times the maximum clinical exposure. The in vivo micronucleus test was negative.
The major metabolite NAP226-90 also did not show a genotoxic potential.
No evidence of carcinogenicity was found in studies in mice and rats at the maximum
tolerated dose, although the exposure to rivastigmine and its metabolites was lower
than the human exposure. When normalised to body surface area, the exposure to
rivastigmine and its metabolites was approximately equivalent to the maximum
recommended human dose of 12 mg/day; however, when compared to the maximum
human dose, a multiple of approximately 6-fold was achieved in animals.
In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in
pregnant rats and rabbits gave no indication of teratogenic potential on the part of
rivastigmine. In oral studies with male and female rats, no adverse effects of

rivastigmine were observed on fertility or reproductive performance of either the
parent generation or the offspring of the parents.
A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Capsule content:
Microcrystalline cellulose (E460)
Hypromellose (E464)
Silica, colloidal anhydrous (E551)
Magnesium stearate (E470b)
Capsule shell:
Iron oxide yellow (E172)
Titanium dioxide (E171)
Gelatine (E441)
Iron oxide red (E172)
Printing ink containing:
Shellac
Propylene glycol
Iron oxide black (E172)
Potassium hydroxide

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
4 Years

6.4

Special precautions for storage
Do no store above 30°C

6.5

Nature and contents of container
The product is packed in transparent PVC/Aluminium blisters.
The blisters are subsequently packed into cardboard boxes in pack sizes of 14,
28, 56 and 112 hard capsules.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
No special requirements for disposal.

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Ltd
Units 3 & 4, Quidhampton Business Units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 20416/0239

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21/06/2012

10

DATE OF REVISION OF THE TEXT
29/12/2015

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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