PROMETAX 2mg / ml oral solution medication leaflet

Prometax 2 mg/ml oral solution

Each ml contains rivastigmine hydrogen tartrate corresponding to 2 mg rivastigmine.

Each 3 ml oral solution contains 3 mg of sodium benzoate (E211).

For the full list of excipients, see section 6.1.

Oral solution

Clear, yellow solution.

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 and treatmentof Alzheimer’s dementia or dementia associated with Parkinson’s disease. Diagnosis should be madeaccording to current guidelines. Therapy with rivastigmine should only be started if a caregiver isavailable who will regularly monitor intake of the medicinal product by the patient.

Rivastigmine oral solution should be administered twice a day, with morning and evening meals. Theprescribed amount of solution should be withdrawn from the container using the oral dosing syringesupplied. Rivastigmine oral solution may be swallowed directly from the syringe. Rivastigmine oralsolution and rivastigmine capsules may be interchanged at equal doses.

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 then 6 mgtwice a day should also be based on good tolerability of the current dose and may be considered after aminimum 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. Ifadverse 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 should bemaintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice aday.

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 treatment thepatient’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 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.

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 toindividual tolerability should be closely followed as patients with clinically significant renal or hepaticimpairment might experience more dose-dependent adverse reactions. Patients with severe hepaticimpairment have not been studied, however, Prometax oral solution may be used in this patientpopulation provided close monitoring is exercised (see sections 4.4 and 5.2).

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

Hypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of theexcipients listed in section 6.1.

Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigminepatch (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, Prometax 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.

Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade depointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk ofdeveloping torsade de pointes; for example, those with uncompensated heart failure, recent myocardialinfarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitantuse with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections4.5 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 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 recommended intreating 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 or severityof tremor have been observed in patients with dementia associated with Parkinson’s disease (see section4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due totremor 1.7% on rivastigmine vs 0% on placebo). Clinical monitoring is recommended for these adversereactions.

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 beclosely followed. Patients with severe hepatic impairment have not been studied. However, Prometaxmay 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 likelyto discontinue due to adverse reactions.

One of the excipients in Prometax oral solution is sodium benzoate (E211). Benzoic acid is a mildirritant to the skin, eyes and mucous membrane.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially'sodium-free'.

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type musclerelaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible doseadjustments 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 antiarrhythmic agents,calcium channel antagonists, digitalis glycoside, pilocarpin).

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

No pharmacokinetic interaction was observed between rivastigmine and digoxin, warfarin, diazepam orfluoxetine in studies in healthy volunteers. The increase in prothrombin time induced by warfarin is notaffected by administration of rivastigmine. No untoward effects on cardiac conduction were observedfollowing 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 this occursin humans. No clinical data on exposed pregnancies are available. In peri/postnatal studies in rats, anincreased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearlynecessary.

In animals, rivastigmine is excreted in milk. It is not known if rivastigmine is excreted into human milk.

Therefore, women on rivastigmine should not breast-feed.

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

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

The most commonly reported adverse reactions (ADRs) are gastrointestinal, including nausea (38%) andvomiting (23%), especially during titration. Female patients in clinical studies were found to be moresusceptible 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 Prometax.

Table 1

Very rare Urinary infection

Very common Anorexia

Common Decreased appetite

Not known Dehydration

Common Nightmares

Common Agitation

Common Confusion

Common Anxiety

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 (including worsening of

Parkinson’s disease)

Rare Angina pectoris

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

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 were associated withoesophageal rupture (see section 4.4).

Uncommon Elevated liver function tests

Not known Hepatitis

Common Hyperhydrosis

Rare Rash

Not known Pruritus, allergic dermatitis (disseminated)

Common Fatigue and asthenia

Common Malaise

Uncommon Fall

Common Weight loss

The following additional adverse reactions have been observed with Prometax 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 dementiaassociated with Parkinson’s disease treated with Prometax 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

Common Bradycardia

Uncommon Atrial 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)

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 Prometax transdermal patches: agitation (common).

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conductedwith Prometax in patients with dementia associated with Parkinson’s disease with pre-defined adverseevents that may reflect worsening of parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect worsening Prometax Placeboof parkinsonian symptoms in patients with dementia n (%) n (%)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, vomiting anddiarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntaryurination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

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

Additionaly 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 inhibition ofabout 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmineshould 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 shouldbe given as necessary.

In massive overdose, atropine can be used. An initial dose of 0.03 mg/kg intravenous atropine sulphate isrecommended, with subsequent doses based on clinical response. Use of scopolamine as an antidote isnot 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-

Cog with no worsening on

CIBIC-Plus and PDS

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

Clinical studies in dementia associated with Parkinson’s disease

The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated 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, ameasure 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- ADCS-CGIC

Parkinson’s Disease Prometax Placebo CGIC Placebo

Prometax

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 2.1 ± 8.2 -0.7 ± 7.5 3.8 ± 1.4 4.3 ± 1.5± SD

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 at 24 weeks 2.5 ± 8.4 -0.8 ± 7.5 3.7 ± 1.4 4.3 ± 1.5± SD

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. Apositive 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 Prometax Placebo Prometax 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 at 24 weeks 1.0 ± 9.2 -2.1 ± 8.3 2.6 ± 7.6 0.1 ± 6.9± SD

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 at 24 weeks 2.6 ± 9.4 -1.8 ± 7.2 1.9 ± 7.7 -0.2 ± 7.5± SD

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. Apositive 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

Prometax 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. Absolutebioavailability after a 3 mg dose is about 36%  13%. Administration of rivastigmine oral solution withfood delays absorption (tmax) by 74 min and lowers Cmax by 43% and increases AUC by approximately9%.

Protein binding of rivastigmine is approximately 40%. It readily crosses the blood brain barrier and hasan 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 route ofelimination. Following administration of 14C-rivastigmine, renal elimination was rapid and essentiallycomplete (>90%) within 24 hours. Less than 1% of the administered dose is excreted in the faeces. Thereis no accumulation of rivastigmine or the decarbamylated metabolite in patients with Alzheimer’sdisease.

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

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 renal impairmentcompared with healthy subjects; however there were no changes in Cmax and AUC of rivastigmine insubjects 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 to humanexposure 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 maximum clinicalexposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did notshow 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 rats andrabbits gave no indication of teratogenic potential on the part of rivastigmine. In oral studies with maleand 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.

Sodium benzoate (E211)

Citric acid

Sodium citrate

Quinoline yellow WS dye (E104)

Purified water

Not applicable.

3 years

Prometax oral solution should be used within 1 month of opening the bottle.

Do not store above 30°C. Do not refrigerate or freeze.

Store in an upright position.

Type III amber glass bottle with a child-resistant cap, dip tube and self aligning plug. 50 ml or 120 mlbottle. The oral solution is packaged with an oral dosing syringe in a plastic tube container.

The prescribed amount of solution should be withdrawn from the bottle using the oral dosing syringesupplied.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/98/092/013

EU/1/98/092/018

Date of first authorisation: 04 December 1998

Date of latest renewal: 21 May 2008

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

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