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.

Dosage regimen

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

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

Maintenance dose

1.5 mg 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

6 mg twice a day.

Re-initiation of therapy

The incidence and severity of adverse events are generally increased with higher doses.

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.

Special populations

Renal and hepatic impairment

No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more dose‑dependent adverse reactions.

Patients with severe hepatic impairment have not been studied, however, Exelon capsules may be used in this patient population provided close monitoring is exercized (see sections 4.4 and 5.2).

Paediatric patients (below 18 years)

The use of Exelon in pediatric patients has not been studied and is therefore not recommended.

Method of administration

Exelon hard capsules should be administered twice a day, with morning and evening meals.

Exelon oral solution and Exelon capsules may be interchanged at equal doses.

Treatment should always be started at a dose of 1.5 mg twice daily and titrated to the patient’s maintenance dose. If treatment is interrupted for longer than three days, treatment should be re-initiated with the lowest daily dose to reduce the possibility of adverse reactions (e.g., severe vomiting) (4.2  Posology and method of administration).

Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose .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 (see section 4.8).

Patients with Alzheimer’s disease may lose weight. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. The patient’s weight should be monitored during therapy with Exelon.

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

As with other cholinomimetics, care must be taken when using Exelon in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Cholinergic stimulation may cause increased gastric acid secretion and may exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such conditions.

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

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

In patients with dementia associated with Parkinson’s disease who were treated with Exelon capsules worsening of parkinsonian symptoms, particularly tremor, has been observed (see section 4.8).

QT prolongation and torsade de pointes

Electrocardiogram QT prolongation may occur in patients treated with certain cholinesterase inhibitor products including 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, hypokalemia or hypomagnesemia, personal or family history of QT prolongation, or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes. Clinical monitoring may also be required (see section INTERACTIONS).

Skin reactions

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

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).

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.

Special populations

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

Rivastigmine is metabolized mainly through hydrolysis by esterases. Minimal metabolism occurs via the major cytochrome P450 isoenzymes. Thus, no pharmacokinetic interactions are anticipated with other drugs metabolized by these enzymes.

Anticipated interactions resulting in a concomitant use not recommended

Metoclopramide

Considering the possibility of an additive extra-pyramidal effect the concomitant use of metoclopramide and rivastigmine is not recommended.

Drugs acting on cholinergic system

In view of its pharmacodynamic effects, rivastigmine should not be given concomitantly with other cholinomimetic drugs due to possible additive effect. Rivastigmine might also interfere with the activity of anticholinergic medications (e.g., oxybutynin, tolterodine).

Succinylcholine-type muscle relaxants

As a cholinesterase inhibitor, rivastigmine may exaggerate the effects of succinylcholine-type muscle relaxants during anaesthesia

Anticipated interactions to be considered

Medicinal products known to prolong the QT interval

Caution is advised when rivastigmine is used in combination with other medicinal products known to prolong the QT interval (including but not limited to quinidine, amiodarone, pimozide, halofantrine, cisapride, citalopram, mizolastin, moxifloxacin, erythromycin). Clinical monitoring may also be required (see section WARNINGS AND PRECAUTIONS).

Observed interactions to be considered

Beta-blockers

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.

Nicotine

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

Interactions with commonly used concomitant drugs

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.

Concomitant administration of rivastigmine with commonly prescribed medications, such as antacids, antiemetics, antidiabetics, centrally acting antihypertensives, calcium channel blockers, inotropic drugs, antianginals, non-steroidal anti-inflammatory drugs, oestrogens, analgesics, benzodiazepines, and antihistamines, was not associated with an alteration in the kinetics of rivastigmine, or an increased risk of clinically relevant untoward effects.

Pregnancy

Risk Summary

The safety of Exelon in human pregnancy has not been established. In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans. In animal studies, rivastigmine was not teratogenic. Exelon should only be given to pregnant women if the potential benefit outweighs the potential risk for the fetus.

Animal data

Embryo-fetal toxicity studies in pregnant rats and rabbits with oral dose levels up to 2.3 mg base/kg/day revealed no evidence of teratogenic potential for rivastigmine. In pre- and post-natal studies, there was no evidence of adverse effects of rivastigmine on fertility, reproductive performance or in utero or postnatal growth and development in rats at dose levels up to 1.1 mg base/kg/day.

Lactation

It is not known if Exelon is transferred into human milk. In animals, rivastigmine and/or metabolites were transferred into breast milk. patients on Exelon should therefore not breast-feed.

Females and males of reproductive potential

There is no information available on the effects of rivastigmine in women of child-bearing potential.

Fertility

There is no information available on the effect of rivastigmine on human fertility. In male and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive performance of either the parents or their offspring.

Alzheimer’s and Parkinson’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 Therefore, , in patients with dementia treated with Exelon ,the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse drug reactions from clinical trials in Table 1 and Table 2 are listed according to MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1

Table 2 Adverse drug reactions reported during a 24-week period in clinical studies conducted in patients with dementia associated with Parkinson’s disease treated with Exelon hard capsules

Additional adverse reactions observed during a 76-week prospective, open-label study in patients with dementia associated with Parkinson’s disease treated with Exelon capsules: hypertension, hypotension (common).

The following additional adverse drug reactions have been reported in a clinical study in patients with dementia associated with Parkinson’s disease treated with Exelon Patch: agitation, depression (common).

Additional adverse drug reactions from post-marketing spontaneous reports (frequency not known)

The following additional adverse drug reactions have been identified with Exelon hard capsules or Exelon oral solution based on post-marketing spontaneous reports. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency.

Frequency not known: dehydration, aggression, restlessness, extrapyramidal symptoms in patients with Alzheimer’s dementia, sick sinus syndrome, hepatitis, allergic dermatitis (disseminated).

Additional adverse drug reactions which have been reported with Exelon Patch

Common: urinary incontinence.

Uncommon: cerebrovascular accident, delirium, psychomotor hyperactivity.

Rarely reported: erythema, urticaria, blister, allergic dermatitis (localized).

Information from clinical trials in patients with dementia associated with Parkinson’s disease

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

Table 3                Pre-defined events that may reflect worsening of Parkinson’s disease in patients with dementia associated with Parkinson’s disease (Study B2311)

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

-To reports any side effect(s):

·    Saudi Arabia:

Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +996112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com 

•    Other GCC States:

-  Please contact the relevant competent authority.

Symptoms

Most cases of accidental overdose have not been associated with any clinical signs or symptoms and almost all of the patients concerned continued rivastigmine treatment. Where symptoms have occurred, they have included nausea, vomiting, diarrhea, abdominal pain, dizziness, tremor, headache, somnolence, bradycardia, confusional state, hyperhidrosis, hypertension, hallucinations, and malaise. Overdosage with cholinesterase inhibitors can result in cholinergic crisis characterized by severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, and convulsions. Muscle weakness is a possibility and may result in death if respiratory muscles are involved. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur.

Fatal outcome has been rarely reported with rivastigmine overdose and the relationship to rivastigmine was unclear. Symptoms of overdose and outcome vary from patient to patient and the severity of the outcome is not predictably related to the amount of the overdose.

Treatment

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

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

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

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

Clinical studies in dementia associated with Parkinson’s disease

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

Table 5

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

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 Exelon 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).

Absorption

Rivastigmine is rapidly and completely absorbed. Peak plasma concentrations are reached in approximately 1 hour. As a consequence of rivastigmine’s interaction with its target enzyme, the increase in bioavailability is about 1.5-fold greater than that expected from the increase in dose. Absolute bioavailability after a 3 mg dose is about 36%±13%. Administration of rivastigmine with food delays absorption (t_max) by 90 min and lowers C_max and increases AUC by approximately 30%.

Distribution

Rivastigmine is weakly bound to plasma proteins (approximately 40%). Rivastigmine distributes equally between blood and plasma with a blood-to-plasma partition ratio of 0.9 at concentrations ranging from 1 to 400 ng/mL. It readily crosses the blood brain barrier reaching peak concentrations in 1 to 4 hours, and with a cerebrospinal fluid-to-plasma AUC ratio of 40%. Rivastigmine has a volume of distribution after iv dosing in the range of 1.8-2.7 L/kg.

Biotranformation

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

Based on in vitro studies, no pharmacokinetic interaction is expected with medicinal products metabolised by the following cytochromes isoemzymes: CYP1A2, CYP2D6, CYP3A4/5, CYP2E1, CYP2C9, CYP2C8, CYP2C19, or CYP2B6. Based on evidence from animal studies the major cytochrome P450 isoenzymes are minimally involved in rivastigmine metabolism. Consistent with these observations is the finding that no drug interactions relating to cytochrome P450 have been observed in humans (see section INTERACTIONS).

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.

Special population

Elderly subjects

In a study to assess the effect of age on the pharmacokinetics of 1 and 2.5 mg oral rivastigmine, plasma concentrations of rivastigmine tended to be higher in the elderly (n=24, aged 61 to 71 years) as compared to young subjects (n=24, aged 19 to 40 years) after the 1 mg dose. This difference was more pronounced with the higher dose (2.5 mg) at which rivastigmine plasma concentrations were 30% greater in the healthy elderly than in healthy young subjects. Plasma levels of the decarbamylated phenolic metabolite were not substantially affected by age. Studies in in Alzheimer patients aged between 50 and 92 years showed no change in bioavailability with age.

Renal impairment

Plasma levels of rivastigmine were reported not to differ significantly between patients with severe renal impairment (n=10, glomerular filtration rate (GFR) <10 mL/minute) and control subjects (n=10, GFR ≥60 mL/min) given a single oral dose of 3 mg. Clearance of rivastigmine was 4.8 L/min and 6.9 L/min in patients and healthy subjects, respectively. However, in moderately impaired renal patients (n=8, GFR=10 to 50 mL/min), peak plasma concentrations of rivastigmine were increased by almost 2.5-fold and overall plasma levels (AUC) of the decarbamylated phenolic metabolite were increased by approximately 50%. Clearance of rivastigmine was 1.7 L/min. The reason for this discrepancy between severely and moderately impaired renal patients is unclear (see section DOSAGE REGIMEN AND ADMINISTRATION and section WARNINGS AND PRECAUTIONS).

Hepatic impairment

After oral administration, the C_max of rivastigmine was approximately 60% higher and the AUC more than twice as high in subjects with mild to moderate hepatic impairment compared to healthy subjects. Following a single 3-mg dose or multiple 6-mg twice a day doses, the mean oral clearance of rivastigmine was approximately 60 to 65% lower in mild (n=7, Child-Pugh score 5 to 6) and moderate (n=3, Child-Pugh score 7 to 9) hepatically impaired patients (n=10, biopsy proven) than in healthy subjects (n=10). These pharmacokinetic changes had no effect on either the incidence or severity of adverse effects (See section DOSAGE REGIMEN AND ADMINISTRATION and section WARNINGS AND PRECAUTIONS).

Clinical studies in Alzheimer’s Dementia

The efficacy of Exelon in the treatment of Alzheimer’s Disease has been demonstrated in placebo-controlled studies. The patients involved had an MMSE (Mini-Mental State Examination) of 10 to 24. Results from two pivotal 26-week multicenter studies comparing 1 to 4 mg/day and 6 to 12 mg/day with placebo, as well as pooled analysis of Phase III studies have established that Exelon produces significant improvement in the major domains of cognition, global functioning, and activities of daily living, and in disease severity. Both the low and high dose ranges showed benefit for cognition, global functioning, and disease severity; in addition, the higher dose range produced benefit in activities of daily living.

The following key outcome measures were used in these studies:

Alzheimer's Disease Assessment Scale (ADAS-Cog): a performance-based test system that measures cognitive areas relevant for patients with Alzheimer's Disease such as attention, learning, memory, and language.

Clinician Interview Based Impression of Change-Plus (CIBIC-Plus): a clinician-rated assessment of the patient’s global change in the domains of cognition, behaviour, and functioning, incorporating separate patient and caregiver inputs.

Progressive Deterioration Scale (PDS): a caregiver-rated evaluation of the patient's ability to perform activities of daily living such as toileting, washing, eating, and helping with household chores and shopping.

Study results have indicated that onset of efficacy is generally as early as week 12 and is maintained at the end of 6 months of treatment. Patients treated with 6 to 12 mg experienced improvement in cognition, activities of daily living and global functioning, while placebo patients showed deterioration. The effects of Exelon on these measures (e.g., ADAS-Cog difference from placebo 5 points at week 26) indicate a delay in the rate of deterioration of at least 6 months.

Analyses performed to detect those subtests and symptoms of the ADAS-Cog and CIBIC-Plus, respectively, which improved in patients treated with Exelon indicated that all ADAS-Cog subtests (ideational praxis, orientation, test instructions, word recall, language ability and word recognition) and all CIBIC-Plus items, except anxiety, were significantly improved at week 26 with Exelon 6 to 12 mg. Items which improved in at least 15% more Exelon than placebo patients completing treatment included word recall, functioning, agitation, tearfulness or crying, delusions, hallucinations, purposeless and inappropriate activities, and physical threats and/or violence.

Similar results were observed with Exelon capsule 6 mg twice a day in a controlled study in Chinese patients with mild to moderately severe Alzheimer’s dementia.

Clinical studies in dementia associated with Parkinson’s disease

The efficacy of rivastigmine in dementia associated with Parkinson’s disease has been demonstrated in a 24-week multi-center, double blind, placebo-controlled core study and its 24-week open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) of 10 to 24. Efficacy has been established by the use of two independent scales which were assessed at regular intervals during a 6-month treatment period as reported in Table 4 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 4                Dementia associated with Parkinson’s Disease

NON-CLINICAL SAFETY DATA

Acute toxicity

The estimated oral LD₅₀ values in mice were 5.6 mg base/kg (males) and 13.8 mg base/kg (females). The estimated oral LD₅₀ values in rats were 8.1 mg base/kg (males) and 13.8 mg base/kg (females).

Repeated dose toxicity

Studies in rats, mice, dogs, minipigs and monkeys (maximum doses 3.8, 6.3, 2.5, 6.0 and 6.3 mg-base/kg/day, respectively) revealed evidence of cholinergic stimulation of the central and peripheral nervous systems. In-life tolerability to rivastigmine was variable between species, with the dog as the most sensitive species. No target organ toxicities or clinical pathology alterations were observed in any species, although gastro-intestinal effects were prominent in dogs.

Mutagenicity

Rivastigmine was not mutagenic in in vitro tests for gene mutations and primary DNA damage. In tests for chromosomal damage in vitro, a small increase in the number of cells carrying chromosomal aberrations occurred at very high concentrations. However, as there was no evidence of clastogenic activity in the more relevant in vivo micronucleus test assessing chromosomal damage, it is most likely that the in vitro findings were false positive observations. In addition, the major metabolite NAP226-90 did not induce structural chromosome aberrations in an in vitro test indicating that the compound has no genotoxic potential.

Carcinogenicity

No evidence of carcinogenicity was found in oral and topical studies in mice and in oral study in rats at the maximum tolerated dose. The exposure to rivastigmine and its major metabolite was approximately equivalent to human exposure with highest doses of rivastigmine capsules and patches.

Reproductive toxicity

See section PREGNANCY, LACTATION, FEMALES AND MALES OF REPRODUCTIVE POTENTIAL.

Local tolerance

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

Gelatin

Magnesium stearate

Hypromellose

Microcrystalline cellulose

Silica, colloidal anhydrous

Yellow iron oxide (E172)

Red iron oxide (E172)

Titanium dioxide (E171)

Shellac

Not applicable.

Do not store above 30°C.

-                Blister of clear PVC tray with blue lidding foil with 14 capsules. Each box contains 28, 56 or 112 capsules.

-                HDPE bottles with plastic closure with induction innerseal. Each bottle contains 250 capsules.

Not all pack sizes may be marketed.

No special requirements.