RIVASTIGMINA SANDOZ 4.5mg capsules medication leaflet

Rivastigmine Sandoz 1.5 mg hard capsules

Rivastigmine Sandoz 3 mg hard capsules

Rivastigmine Sandoz 4.5 mg hard capsules

Rivastigmine Sandoz 6 mg hard capsules

Each capsule contains rivastigmine hydrogen tartrate corresponding to 1.5 mg rivastigmine.

Each capsule contains rivastigmine hydrogen tartrate corresponding to 3 mg rivastigmine.

Each capsule contains rivastigmine hydrogen tartrate corresponding to 4.5 mg rivastigmine.

Each capsule contains rivastigmine hydrogen tartrate corresponding to 6 mg rivastigmine.

For the full list of excipients, see section 6.1.

Hard capsule

Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint“RIV 1.5 mg” on the body.

Off-white to slightly yellow powder in a capsule with orange cap and orange body, with red imprint“RIV 3 mg” on the body.

Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint“RIV 4.5 mg” on the body.

Off-white to slightly yellow powder in a capsule with red cap and orange body, with red imprint“RIV 6 mg” on the body.

Symptomatic treatment of mild to moderately severe Alzheimer’s dementia.

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson’sdisease.

Treatment should be initiated and supervised by a physician experienced in the diagnosis andtreatment of Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis shouldbe made according to current guidelines. Therapy with rivastigmine should only be started if acaregiver 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 capsulesshould be swallowed whole.

Initial dose1.5 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 oftreatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then6 mg twice a day should also be based on good tolerability of the current dose and may be consideredafter 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 orworsening 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-tolerateddose or the treatment may be discontinued.

The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients shouldbe maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mgtwice 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 forpatients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatmentthe patient’s rate of decline in dementia symptoms is not altered favourably, the treatment should bediscontinued. Discontinuation should also be considered when evidence of a therapeutic effect is nolonger present.

Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seenin 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.

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 accordingto individual tolerability should be closely followed as patients with clinically significant renal orhepatic impairment might experience more dose-dependent adverse reactions. Patients with severehepatic impairment have not been studied, however, rivastigmine capsules may be used in this patientpopulation provided close monitoring is exercised (see sections 4.4 and 5.2).

There is no relevant use of rivastigmine in the paediatric population in the treatment of Alzheimer’sdisease.

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

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

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

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

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patchsize, 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 thesecases, treatment should be discontinued (see section 4.3).

Patients who develop application site reactions suggestive of allergic contact dermatitis to rivastigminepatch and who still require rivastigmine treatment should only be switched to oral rivastigmine afternegative allergy testing and under close medical supervision. It is possible that some patientssensitised to rivastigmine by exposure to rivastigmine patch may not be able to take rivastigmine inany 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’sdementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementiaassociated with Parkinson’s disease) have been observed shortly after dose increase. They mayrespond 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 occurparticularly when initiating treatment and/or increasing the dose (see section 4.8). These adversereactions occur more commonly in women. Patients who show signs or symptoms of dehydrationresulting from prolonged vomiting or diarrhoea can be managed with intravenous fluids and dosereduction or discontinuation if recognised and treated promptly. Dehydration can be associated withserious 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 bemonitored.

In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments asrecommended in section 4.2 must be made. Some cases of severe vomiting were associated withoesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose incrementsor high doses of rivastigmine.

Care must be taken when using rivastigmine in patients with sick sinus syndrome or conductiondefects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Electrocardiogram QT prolongation may occur in patients treated with certain cholinesterase inhibitorproducts including rivastigmine. Rivastigmine may cause bradycardia which constitutes a risk factorin the occurrence of torsade de pointes, predominantly in patients with risk factors. Caution is advisedin patients with pre-existing, or a family history of, QTc prolongation or at higher risk of developingtorsade de pointes; for example, those with uncompensated heart failure, recent myocardial infarction,bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant use withmedicinal products known to induce QT prolongation - or torsade de pointes. Clinical monitoring(ECG) may also be required (see sections 4.5 and 4.8).

Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patientswith 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 orobstructive pulmonary disease.

Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommendedin 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-relatedcognitive decline) has not been investigated and therefore use in these patient populations is notrecommended.

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms.

Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence orseverity 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 isrecommended for these adverse reactions.

Patients with clinically significant renal or hepatic impairment might experience more adversereactions (see sections 4.2 and 5.2). Dosing recommendations to titrate according to individualtolerability must be closely followed. Patients with severe hepatic impairment have not been studied.

However, rivastigmine 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 morelikely to discontinue due to adverse reactions.

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type musclerelaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possibledose adjustments or temporarily stopping treatment can be considered if needed.

In view of its pharmacodynamic effects and possible additive effects, rivastigmine should not be givenconcomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity ofanticholinergic medicinal products (e.g. oxybutynin, tolterodine).

Additive effects leading to bradycardia (which may result in syncope) have been reported with thecombined 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 inpatients using other beta-blockers. Therefore, caution should be exercised when rivastigmine iscombined with beta-blockers and also other bradycardia agents (e.g.class III antiarrhythmicagents, calcium channel antagonists, digitalis glycoside, pilocarpin).

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

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepamor fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin isnot affected by administration of rivastigmine. No untoward effects on cardiac conduction wereobserved 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.

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

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

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.

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

The most commonly reported adverse reactions (ADRs) are gastrointestinal, including nausea (38%)and vomiting (23%), especially during titration. Female patients in clinical studies were found to bemore susceptible than male patients to gastrointestinal adverse reactions and weight loss.

Adverse reactions in Table 1 and Table 2 are listed according to MedDRA system organ class andfrequency category. Frequency categories are defined using the following convention: very common(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000);very rare (<1/10,000); not known (cannot be estimated from the available data).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with

Alzheimer’s dementia treated with rivastigmine.

Table 1

Very rare Urinary infection

Very common Anorexia

Common Decreased appetite

Not known Dehydration

Common Agitation

Common Confusion

Common Anxiety

Common Nightmares

Uncommon Insomnia

Uncommon Depression

Very rare Hallucinations

Not known Aggression, restlessness

Very common Dizziness

Common Headache

Common Somnolence

Common Tremor

Uncommon Syncope

Rare Seizures

Very rare Extrapyramidal symptoms (includingworsening of Parkinson’s disease)

Not known Pleurothotonus (Pisa syndrome)

Rare Angina pectoris

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

Not known Sick sinus syndrome

Very rare Hypertension

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 wereassociated with oesophageal rupture(see section 4.4).

Uncommon Elevated liver function tests

Not known Hepatitis

Common Hyperhydrosis

Rare Rash

Not known Pruritus, allergic dermatitis (disseminated)

General disorders and administration siteconditions

Common Fatigue and asthenia

Common Malaise

Uncommon Fall

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 withdementia associated with Parkinson’s disease treated with rivastigmine capsules.

Table 2

Common Decreased appetite

Common Dehydration

Common Insomnia

Common Anxiety

Common Restlessness

Common Hallucination, visual

Common Depression

Not known Aggression

Very common Tremor

Common Dizziness

Common Somnolence

Common Headache

Common Parkinson’s disease (worsening)

Common Bradykinesia

Common Dyskinesia

Common Hypokinesia

Common Cogwheel rigidity

Uncommon Dystonia

Not known Pleurothotonus (Pisa syndrome)

Common Bradycardia

Uncommon Arial fibrillation

Uncommon Atrioventricular block

Not known Sick sinus syndrome

Common Hypertension

Uncommon Hypotension

Very common Nausea

Very common Vomiting

Common Diarrhoea

Common Abdominal pain and dyspepsia

Common Salivary hypersecretion

Not known Hepatitis

Common Hyperhydrosis

Not known Allergic dermatitis (disseminated)

General disorders and administration siteconditions

Very common Fall

Common Fatigue and asthenia

Common Gait disturbance

Common Parkinson gait

The following additional adverse reaction has been observed in a study of patients with dementiaassociated 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 conductedwith rivastigmine in patients with dementia associated with Parkinson’s disease with pre-definedadverse events that may reflect worsening of parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect Rivastigmine Placeboworsening of parkinsonian symptoms in n (%) n (%)patients with dementia associated with

Parkinson’s disease

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Most cases of accidental overdose have not been associated with any clinical signs or symptoms andalmost 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 moderatepoisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomitingand 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.

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibitionof about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose ofrivastigmine should be administered for the next 24 hours. In overdose accompanied by severe nauseaand vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adversereactions should be given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphateis recommended, with subsequent doses based on clinical response. Use of scopolamine as an antidoteis not recommended.

Pharmacotherapeutic group: psychoanaleptics, anticholinesterases, ATC code: N06DA03

Rivastigmine is an acetyl- and butyrylcholinesterase inhibitor of the carbamate type, thought tofacilitate cholinergic neurotransmission by slowing the degradation of acetylcholine released byfunctionally intact cholinergic neurones. Thus, rivastigmine may have an ameliorative effect oncholinergic-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 thattemporarily inactivates the enzymes. In healthy young men, an oral 3 mg dose decreasesacetylcholinesterase (AChE) activity in CSF by approximately 40% within the first 1.5 hours afteradministration. Activity of the enzyme returns to baseline levels about 9 hours after the maximuminhibitory effect has been achieved. In patients with Alzheimer’s disease, inhibition of AChE in CSFby rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested. Inhibitionof butyrylcholinesterase activity in CSF of 14 Alzheimer patients treated by rivastigmine was similarto that of AChE.

Clinical studies in Alzheimer’s dementia

The efficacy of rivastigmine has been established through the use of three independent, domainspecific, 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, aperformance 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 incorporatingcaregiver input), and the PDS (Progressive Deterioration Scale, a caregiver-rated assessment of theactivities of daily living including personal hygiene, feeding, dressing, household chores such asshopping, retention of ability to orient oneself to surroundings as well as involvement in activitiesrelating 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 threepivotal 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 asat 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 definitionof 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 mggroup, corresponding to this definition, was 9.3 mg. It is important to note that the scales used in thisindication 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 Placebo Rivastigmine Placebo6-12 mg 6-12 mg

N=473 N=472 N=379 N=444

ADAS-Cog: improvement 21*** 12 25*** 12of at least 4 points

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

PDS: improvement of at 26*** 17 30*** 18least 10%

At least 4 points 10* 6 12** 6improvement on ADAS-Cogwith no worsening on

CIBIC-Plus and PDS

*p<0.05, **p<0.01, ***p<0.001

Clinical studies in dementia associated with Parkinson’s disease

The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated ina 24-week multicentre, double-blind, placebo-controlled core study and its 24-week open-labelextension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) scoreof 10-24. Efficacy has been established by the use of two independent scales which were assessed atregular 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 ADAS-Cog ADAS-Cog ADCS-CGIC ADCS-CGIC

Parkinson’s Disease Rivastigmine Placebo Rivastigmine 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 at24 weeks ± SD 2.1 ± 8.2 -0.7 ± 7.5 3.8 ± 1.4 4.3 ± 1.5

Adjusted treatmentdifference 2.881 n/ap-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 at24 weeks ± SD 2.5 ± 8.4 -0.8 ± 7.5 3.7 ± 1.4 4.3 ± 1.5

Adjusted treatmentdifference 3.541 n/ap-value versus placebo <0.0011 <0.00121 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 alarger treatment effect relative to placebo was seen in the subgroup of patients with moderate dementiaassociated with Parkinson’s disease. Similarly a larger treatment effect was observed in those patientswith visual hallucinations (see Table 6).

Table 6

Dementia associated with ADAS-Cog ADAS-Cog ADAS-Cog ADAS-Cog

Parkinson’s Disease Rivastigmine Placebo Rivastigmine Placebo

Patients with visual Patients without visualhallucinations 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 at24 weeks ± SD 1.0 ± 9.2 -2.1 ± 8.3 2.6 ± 7.6 0.1 ± 6.9

Adjusted treatmentdifference 4.271 2.091p-value versus placebo 0.0021 0.0151

Patients with moderate Patients with mild dementiadementia (MMSE 10-17) (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 at24 weeks ± SD 2.6 ± 9.4 -1.8 ± 7.2 1.9 ± 7.7 -0.2 ± 7.5

Adjusted treatmentdifference 4.731 2.141p-value versus placebo 0.0021 0.01011 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 withrivastigmine in all subsets of the paediatric population in the treatment of Alzheimer’s dementia and inthe treatment of dementia in patients with idiopathic Parkinson’s disease (see section 4.2 forinformation on paediatric use).

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached inapproximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, theincrease 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 withfood delays absorption (tmax) by 90 min and lowers Cmax and increases AUC by approximately 30%.

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier andhas an apparent volume of distribution in the range of 1.8-2.7 l/kg.

Rivastigmine is rapidly and extensively metabolised (half-life in plasma approximately 1 hour),primarily via cholinesterase-mediated hydrolysis to the decarbamylated metabolite. In vitro, thismetabolite shows minimal inhibition of acetylcholinesterase (<10%).

Based on in vitro studies, no pharmacokinetic interaction is expected with medicinal productsmetabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1,

CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from animal studies the majorcytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Total plasmaclearance of rivastigmine was approximately 130 l/h after a 0.2 mg intravenous dose and decreased to70 l/h after a 2.7 mg intravenous dose.

Unchanged rivastigmine is not found in the urine; renal excretion of the metabolites is the major routeof elimination. Following administration of 14C-rivastigmine, renal elimination was rapid andessentially complete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in thefaeces. 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 clearanceof rivastigmine by 23% in patients with Alzheimer’s disease (n=75 smokers and549 non-smokers) following rivastigmine oral capsule doses of up to 12 mg/day.

While bioavailability of rivastigmine is greater in elderly than in young healthy volunteers, studies in

Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

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

Cmax and AUC of rivastigmine were more than twice as high in subjects with moderate renalimpairment compared with healthy subjects; however there were no changes in Cmax and AUC ofrivastigmine in subjects with severe renal impairment.

Repeated-dose toxicity studies in rats, mice and dogs revealed only effects associated with anexaggerated pharmacological action. No target organ toxicity was observed. No safety margins tohuman 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 achromosomal aberration test in human peripheral lymphocytes at a dose 104 times the maximumclinical exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 alsodid 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. Whennormalised to body surface area, the exposure to rivastigmine and its metabolites was approximatelyequivalent to the maximum recommended human dose of 12 mg/day; however, when compared to themaximum 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 ratsand rabbits gave no indication of teratogenic potential on the part of rivastigmine. In oral studies withmale and female rats, no adverse effects of rivastigmine were observed on fertility or reproductiveperformance 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.

Rivastigmine Sandoz 1.5 mg hard capsules:

- Gelatin

- Titanium dioxide (E171)

- Yellow iron oxide (E172)

Capsule fill:

- Microcrystalline cellulose

- Magnesium stearate

- Hypromellose

- Silica, colloidal anhydrous

- Shellac

- Red iron oxide (E172)

Rivastigmine Sandoz 3 mg and 6 mg hard capsules:

- Gelatin

- Titanium dioxide (E171)

- Yellow iron oxide (E172)

- Red iron oxide (E172)

Capsule fill:

- Microcrystalline cellulose

- Magnesium stearate

- Hypromellose

- Silica, colloidal anhydrous

- Shellac

- Red iron oxide (E172)

Rivastigmine Sandoz 4.5 mg hard capsules:

- Gelatin

- Titanium dioxide (E171)

- Yellow iron oxide (E172)

- Red iron oxide (E172)

Capsule fill:

- Microcrystalline cellulose

- Magnesium stearate

- Hypromellose

- Silica, colloidal anhydrous

- Shellac

- Titanium dioxide (E171)

Not applicable.

5 years

Do not store above 30°C.

- Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 2, 4 or8 blisters.

Not all pack sizes may be marketed.

No special requirements.

Sandoz GmbH

Biochemiestraße 10

A-6250 Kundl

Austria

Rivastigmine Sandoz 1.5 mg hard capsules:

EU/1/09/599/001

EU/1/09/599/002

EU/1/09/599/003

Rivastigmine Sandoz 3 mg hard capsules:

EU/1/09/599/005

EU/1/09/599/006

EU/1/09/599/007

Rivastigmine Sandoz 4.5 mg hard capsules:

EU/1/09/599/009

EU/1/09/599/010

EU/1/09/599/011

Rivastigmine Sandoz 6 mg hard capsules:

EU/1/09/599/013

EU/1/09/599/014

EU/1/09/599/015

Date of first authorisation: 11/12/2009

Date of first renewal: 11/07/2014

Detailed information on this medicinal product is available on the website of the European Medicines

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