EXELON 13.3mg / 24h transdermic patch medication leaflet

Exelon 4.6 mg/24 h transdermal patch

Exelon 9.5 mg/24 h transdermal patch

Exelon 13.3 mg/24 h transdermal patch

Exelon 4.6 mg/24 h transdermal patch

Each transdermal patch releases 4.6 mg of rivastigmine per 24 hours. Each transdermal patch of 5 cm2contains 9 mg of rivastigmine.

Exelon 9.5 mg/24 h transdermal patch

Each transdermal patch releases 9.5 mg of rivastigmine per 24 hours. Each transdermal patch of 10 cm2contains 18 mg of rivastigmine.

Exelon 13.3 mg/24 h transdermal patch

Each transdermal patch releases 13.3 mg of rivastigmine per 24 hours. Each transdermal patch of 15 cm2contains 27 mg of rivastigmine.

For the full list of excipients, see section 6.1.

Transdermal patch

Exelon 4.6 mg/24 h transdermal patch

Each transdermal patch is a thin, matrix-type transdermal patch consisting of three layers. The outside ofthe backing layer is beige and labelled with “Exelon”, “4.6 mg/24 h” and “AMCX”.

Exelon 9.5 mg/24 h transdermal patch

Each transdermal patch is a thin, matrix-type transdermal patch consisting of three layers. The outside ofthe backing layer is beige and labelled with “Exelon”, “9.5 mg/24 h” and “BHDI”.

Exelon 13.3 mg/24 h transdermal patch

Each transdermal patch is a thin, matrix-type transdermal patch consisting of three layers. The outside ofthe backing layer is beige and labelled with “Exelon”, “13.3 mg/24 h” and “CNFU”.

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

Treatment should be initiated and supervised by a physician experienced in the diagnosis and treatmentof Alzheimer’s dementia. Diagnosis should be made according to current guidelines. Similar to anytreatment initiated in patients with dementia, therapy with rivastigmine should only be started if acaregiver is available to regularly administer and monitor the treatment.

Transdermal patches Rivastigmine in vivo releaserates per 24 h

Exelon 4.6 mg/24 h 4.6 mg

Exelon 9.5 mg/24 h 9.5 mg

Exelon 13.3 mg/24 h 13.3 mg

Initial dose

Treatment is started with 4.6 mg/24 h.

After a minimum of four weeks of treatment and if well tolerated according to the treating physician, thedose of 4.6 mg/24 h should be increased to 9.5 mg/24 h, the daily recommended effective dose, whichshould be continued for as long as the patient continues to demonstrate therapeutic benefit.

Dose escalation9.5 mg/24 h is the recommended daily effective dose which should be continued for as long as thepatient continues to demonstrate therapeutic benefit. If well tolerated and only after a minimum of sixmonths of treatment at 9.5 mg/24 h, the treating physician may consider increasing the dose to13.3 mg/24 h in patients who have demonstrated a meaningful cognitive deterioration (e.g. decrease inthe MMSE) and/or functional decline (based on physician judgement) while on the recommended dailyeffective dose of 9.5 mg/24 h (see section 5.1).

The clinical benefit of rivastigmine should be reassessed on a regular basis. Discontinuation should alsobe considered when evidence of a therapeutic effect at the optimal dose is no longer present.

Treatment should be temporarily interrupted if gastrointestinal adverse reactions are observed untilthese adverse reactions resolve. Transdermal patch treatment can be resumed at the same dose iftreatment is not interrupted for more than three days. Otherwise treatment should be re-initiated with4.6 mg/24 h.

Switching from capsules or oral solution to transdermal patches

Based on comparable exposure between oral and transdermal rivastigmine (see section 5.2), patientstreated with Exelon capsules or oral solution can be switched to Exelon transdermal patches asfollows:

* A patient on a dose of 3 mg/day oral rivastigmine can be switched to 4.6 mg/24 h transdermalpatches.

* A patient on a dose of 6 mg/day oral rivastigmine can be switched to 4.6 mg/24 h transdermalpatches.

* A patient on a stable and well tolerated dose of 9 mg/day oral rivastigmine can be switched to9.5 mg/24 h transdermal patches. If the oral dose of 9 mg/day has not been stable and welltolerated, a switch to 4.6 mg/24 h transdermal patches is recommended.

* A patient on a dose of 12 mg/day oral rivastigmine can be switched to 9.5 mg/24 h transdermalpatches.

After switching to 4.6 mg/24 h transdermal patches, provided these are well tolerated after a minimum offour weeks of treatment, the dose of 4.6 mg/24 h should be increased to 9.5 mg/24 h, which is therecommended effective dose.

It is recommended to apply the first transdermal patch on the day following the last oral dose.

* Paediatric population: There is no relevant use of Exelon in the paediatric population in thetreatment of Alzheimer’s disease.

* Patients with body weight below 50 kg: Particular caution should be exercised in titratingpatients with body weight below 50 kg above the recommended effective dose of 9.5 mg/24 h(see section 4.4). They may experience more adverse reactions and may be more likely todiscontinue due to adverse reactions.

* Hepatic impairment: Due to increased exposure in mild to moderate hepatic impairment asobserved with the oral formulation, dosing recommendations to titrate according to individualtolerability should be closely followed. Patients with clinically significant hepatic impairmentmay experience more dose-dependent adverse reactions. Patients with severe hepatic impairmenthave not been studied. Particular caution should be exercised in titrating these patients (seesections 4.4 and 5.2).

* Renal impairment: No dose adjustment is necessary for patients with renal impairment (seesection 5.2).

Transdermal patches should be applied once a day to clean, dry, hairless, intact healthy skin on the upperor lower back, upper arm or chest, in a place which will not be rubbed by tight clothing. It is notrecommended to apply the transdermal patch to the thigh or to the abdomen due to decreasedbioavailability of rivastigmine observed when the transdermal patch is applied to these areas of the body.

The transdermal patch should not be applied to skin that is red, irritated or cut. Reapplication to the exactsame skin location within 14 days should be avoided to minimise the potential risk of skin irritation.

Patients and caregivers should be instructed on important administration instructions:

* The previous day’s patch must be removed before applying a new one every day (see section 4.9).

* The patch should be replaced by a new one after 24 hours. Only one patch should be worn at atime (see section 4.9).

* The patch should be pressed down firmly for at least 30 seconds using the palm of the hand untilthe edges stick well.

* If the patch falls off, a new one should be applied for the rest of the day, then it should be replacedat the same time as usual the next day.

* The patch can be used in everyday situations, including bathing and during hot weather.

* The patch should not be exposed to any external heat sources (e.g. excessive sunlight, saunas,solarium) for long periods of time.

* The patch should not be cut into pieces.

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 increasing doses, particularlyat dose changes. If treatment is interrupted for more than three days, it should be re-initiated with4.6 mg/24 h.

Misuse of the medicinal product and dosing errors resulting in overdose

Misuse of the medicinal product and dosing errors with Exelon transdermal patch have resulted inserious adverse reactions; some cases have required hospitalisation, and rarely led to death (see section4.9). Most cases of misuse of the medicinal product and dosing errors have involved not removing theold patch when putting on a new one and the use of multiple patches at the same time. Patients andtheir caregivers must be instructed on important administration instructions for Exelon transdermalpatch (see section 4.2).

Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occurwhen initiating treatment and/or increasing the dose (see section 4.8). These adverse reactions occurmore commonly in women. Patients who show signs or symptoms of dehydration resulting fromprolonged vomiting or diarrhoea can be managed with intravenous fluids and dose reduction ordiscontinuation if recognised and treated promptly. Dehydration can be associated with seriousoutcomes.

Weight loss

Patients with Alzheimer’s disease may lose weight whilst taking cholinesterase inhibitors, includingrivastigmine. The patient’s weight should be monitored during therapy with Exelon transdermalpatches.

Bradycardia

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 and/or torsade de pointes. Clinical monitoring(ECG) may also be required (see sections 4.5 and 4.8).

Other adverse reactions

Care must be taken when prescribing Exelon transdermal patches:

* to patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricularblock) (see section 4.8);

* to patients with active gastric or duodenal ulcers or patients predisposed to these conditionsbecause rivastigmine may cause increased gastric secretions (see section 4.8);

* to patients predisposed to urinary obstruction and seizures because cholinomimetics may induceor exacerbate these diseases;

* to patients with a history of asthma or obstructive pulmonary disease.

Skin application site reactions

Skin application site reactions may occur with rivastigmine patch and are usually mild or moderate inintensity. Patients and caregivers should be instructed accordingly.

These reactions are not in themselves an indication of sensitisation. However, use of rivastigminepatch 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).

Rivastigmine may exacerbate or induce extrapyramidal symptoms.

Contact with the eyes should be avoided after handling Exelon transdermal patches (see section 5.3).

Hands should be washed with soap and water after removing the patch. In case of contact with eyes or ifthe eyes become red after handling the patch, rinse immediately with plenty of water and seek medicaladvice if symptoms do not resolve.

* Patients with body weight below 50 kg may experience more adverse reactions and may bemore likely to discontinue due to adverse reactions (see section 4.2). Carefully titrate andmonitor these patients for adverse reactions (e.g. excessive nausea or vomiting) and considerreducing the maintenance dose to the 4.6 mg/24 h transdermal patch if such adverse reactionsdevelop.

* Hepatic impairment: Patients with clinically significant hepatic impairment may experiencemore adverse reactions. Dosing recommendations to titrate according to individual tolerabilitymust be closely followed. Patients with severe hepatic impairment have not been studied.

Particular caution must be exercised in titrating these patients (see sections 4.2 and 5.2).

No specific interaction studies have been performed with Exelon transdermal patches.

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 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 and moxifloxacineshould be observed with caution and clinical monitoring (ECG) may also be required.

No pharmacokinetic interaction was observed between oral rivastigmine and digoxin, warfarin,diazepam or fluoxetine in studies in healthy volunteers. The increase in prothrombin time induced bywarfarin is not affected by administration of oral rivastigmine. No untoward effects on cardiacconduction were observed following concomitant administration of digoxin and oral rivastigmine.

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

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 machines. Furthermore, rivastigmine may induce syncope or delirium. As a consequence,rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, inpatients with dementia treated with rivastigmine, the ability to continue driving or operating complexmachines should be routinely evaluated by the treating physician.

Application site skin reactions (usually mild to moderate application site erythema), are the mostfrequent adverse reactions observed with the use of Exelon transdermal patch. The next most commonadverse reactions are gastrointestinal in nature including nausea and vomiting.

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

Table 1 displays the adverse reactions reported in 1,670 patients with Alzheimer’s dementia treated inrandomised, double-blind, placebo and active-controlled clinical studies with Exelon transdermalpatches for a duration of 24-48 weeks and from post-marketing data.

Table 1

Common Urinary tract infection

Common Anorexia, decreased appetite

Uncommon Dehydration

Common Anxiety, depression, delirium, agitation

Uncommon Aggression

Not known Hallucinations, restlessness, nightmares

Common Headache, syncope, dizziness

Uncommon Psychomotor hyperactivity

Very rare Extrapyramidal symptoms

Not known Worsening of Parkinson’s disease, seizure, tremor, somnolence,pleurothotonus (Pisa syndrome)

Uncommon Bradycardia

Not known Atrioventricular block, atrial fibrillation, tachycardia, sick sinussyndrome

Not known Hypertension

Common Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain

Uncommon Gastric ulcer

Not known Pancreatitis

Not known Hepatitis, elevated liver function tests

Common Rash

Not known Pruritus, erythema, urticaria, vesicles, allergic dermatitis(disseminated)

Common Urinary incontinence

Common Application site skin reactions (e.g. application site erythema*,application site pruritus*, application site oedema*, application sitedermatitis, application site irritation), asthenic conditions (e.g. fatigue,asthenia), pyrexia, weight decreased

Rare Fall

*In a 24-week controlled study in Japanese patients, application site erythema, application site oedemaand application site pruritus were reported as “very common”.

When doses higher than 13.3 mg/24 h were used in the above-mentioned placebo-controlled study,insomnia and cardiac failure were observed more frequently than with 13.3 mg/24 h or placebo,suggesting a dose effect relationship. However, these events did not occur at a higher frequency with

Exelon 13.3 mg/24 h transdermal patches than with placebo.

The following adverse reactions have only been observed with Exelon capsules and oral solution and notin clinical studies with Exelon transdermal patches: malaise, confusion, sweating increased (common);duodenal ulcers, angina pectoris (rare); gastrointestinal haemorrhage (very rare); and some cases ofsevere vomiting were associated with oesophageal rupture (not known).

Skin irritation

In double-blind controlled clinical trials, application site reactions were mostly mild to moderate inseverity. The incidence of application site skin reactions leading to discontinuation was ≤2.3% in patientstreated with Exelon transdermal patches. The incidence of application site skin reactions leading todiscontinuation was higher in the Asian population with 4.9% and 8.4% in the Chinese and Japanesepopulation respectively.

In two 24-week double-blind, placebo-controlled clinical trials, skin reactions were measured at eachvisit using a skin irritation rating scale. When observed in patients treated with Exelon transdermalpatches, skin irritation was mostly slight or mild in severity. It was rated as severe in ≤2.2% of patientsin these studies and in ≤3.7% of patients treated with Exelon transdermal patches in a Japanese study.

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 of oral rivastigmine have not been associated with any clinical signsor symptoms and almost all of the patients concerned continued rivastigmine treatment 24 hours after theoverdose.

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. Overdose with Exelon transdermal patchresulting from misuse/dosing errors (application of multiple patches at a time) has been reported in thepost-marketing setting and rarely in clinical trials.

As rivastigmine has a plasma half-life of about 3.4 hours and a duration of acetylcholinesteraseinhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose all Exelontransdermal patches should be removed immediately and no further transdermal patch should be appliedfor the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemeticsshould 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 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.

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 oral 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 oralrivastigmine was similar to the inhibition of AChE activity.

Clinical studies in Alzheimer’s dementia

The efficacy of Exelon transdermal patches in patients with Alzheimer’s dementia has beendemonstrated in a 24-week double-blind, placebo-controlled core study and its open-label extensionphase and in a 48-week double-blind comparator study.

24-week placebo-controlled study

Patients involved in the placebo-controlled study had an MMSE (Mini-Mental State Examination)score of 10-20. Efficacy was established by the use of independent, domain-specific assessment toolswhich were applied at regular intervals during the 24-week treatment period. These include the

ADAS-Cog (Alzheimer’s Disease Assessment Scale - Cognitive subscale, a performance-basedmeasure of cognition) and the ADCS-CGIC (Alzheimer’s Disease Cooperative Study - Clinician’s

Global Impression of Change, a comprehensive global assessment of the patient by the physicianincorporating caregiver input), and the ADCS-ADL (Alzheimer’s Disease Cooperative Study -

Activities of Daily Living, a caregiver-rated assessment of the activities of daily living includingpersonal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orientoneself to surroundings as well as involvement in activities related to finances). The 24-week resultsfor the three assessment tools are summarised in Table 2.

Table 2

Exelon Exelon Placebotransdermal patches capsules9.5 mg/24 h 12 mg/day

ITT-LOCF population N = 251 N = 256 N = 282

ADAS-Cog(n=248) (n=253) (n=281)

Mean baseline  SD 27.0  10.3 27.9  9.4 28.6  9.9

Mean change at week 24  SD -0.6  6.4 -0.6  6.2 1.0  6.8p-value versus placebo 0.005*1 0.003*1

ADCS-CGIC(n=248) (n=253) (n=278)

Mean score  SD 3.9  1.20 3.9  1.25 4.2  1.26p-value versus placebo 0.010*2 0.009*2

ADCS-ADL(n=247) (n=254) (n=281)

Mean baseline  SD 50.1  16.3 49.3  15.8 49.2  16.0

Mean change at week 24  SD -0.1  9.1 -0.5  9.5 -2.3  9.4p-value versus placebo 0.013*1 0.039*1

* p≤0.05 versus placebo

ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward1 Based on ANCOVA with treatment and country as factors and baseline value as a covariate.

Negative ADAS-Cog changes indicate improvement. Positive ADCS-ADL changes indicateimprovement.2 Based on CMH test (van Elteren test) blocking for country. ADCS-CGIC scores <4 indicateimprovement.

The results for clinically relevant responders from the 24-week placebo-controlled study are providedin Table 3. Clinically relevant improvement was defined a priori as at least 4-point improvement onthe ADAS-Cog, no worsening on the ADCS-CGIC, and no worsening on the ADCS-ADL.

Table 3

Patients with clinically significant response (%)

Exelon Exelon Placebotransdermal patches capsules9.5 mg/24 h 12 mg/day

ITT-LOCF population N = 251 N = 256 N = 282

At least 4 points 17.4 19.0 10.5improvement on ADAS-Cogwith no worsening on ADCS-

CGIC and ADCS-ADLp-value versus placebo 0.037* 0.004*

*p<0.05 versus placebo

As suggested by compartmental modelling, 9.5 mg/24 h transdermal patches exhibited exposuresimilar to that provided by an oral dose of 12 mg/day.

48-week active comparator controlled study

Patients involved in the active comparator controlled study had an initial baseline MMSE score of10-24. The study was designed to compare the efficacy of the 13.3 mg/24 h transdermal patch againstthe 9.5 mg/24 h transdermal patch during a 48-week double-blind treatment phase in Alzheimer’sdisease patients who demonstrated functional and cognitive decline after an initial 24-48 week open-label treatment phase while on a maintenance dose of 9.5 mg/24 h transdermal patch. Functionaldecline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSEscore of >2 points from the previous visit or a decrease of >3 points from baseline. Efficacy wasestablished by the use of ADAS-Cog (Alzheimer’s Disease Assessment Scale - Cognitive subscale, aperformance-based measure of cognition) and the ADCS-IADL (Alzheimer’s Disease Cooperative

Study - Instrumental Activities of Daily Living) assessing instrumental activities which includemaintaining finances, meal preparation, shopping, ability to orient oneself to surroundings, ability tobe left unattended. The 48-week results for the two assessment tools are summarised in Table 4.

Table 4

Exelon Exelon Exelon 15 cm2 Exelon

Population/Visit 15 cm2 10 cm2 10 cm2

N = 265 N = 271n Mean n Mean DLS 95% CI p-value

M

ADAS-Cog

LOCF Baseline 264 34.4 268 34.9

DB-week 48 Value 264 38.5 268 39.7

Change 264 4.1 268 4.9 -0.8 (-2.1, 0.5) 0.227

ADCS-IADL

LOCF Baseline 265 27.5 271 25.8

Week 48 Value 265 23.1 271 19.6

Change 265 -4.4 271 -6.2 2.2 (0.8, 3.6) 0.002*

CI - confidence interval.

DLSM - difference in least square means.

LOCF - Last Observation Carried Forward.

ADAS-cog scores: A negative difference in DLSM indicates greater improvement in Exelon15 cm2 as compared to Exelon 10 cm2.

ADCS-IADL scores: A positive difference in DLSM indicates greater improvement in Exelon15 cm2 as compared to Exelon 10 cm2.

N is the number of patients with an assessment at baseline (last assessment in the initial open-label phase) and with at least 1 post-baseline assessment (for the LOCF).

The DLSM, 95% CI, and p-value are based on an ANCOVA (analysis of covariance) modeladjusted for country and baseline ADAS-cog score.

* p<0.05

Source: Study D2340-Table 11-6 and Table 11-7

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 (see section4.2 for information on paediatric use).

Absorption of rivastigmine from Exelon transdermal patches is slow. After the first dose, detectableplasma concentrations are observed after a lag time of 0.5-1 hour. Cmax is reached after 10-16 hours.

After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period ofapplication. With multiple dosing (such as at steady state), after the previous transdermal patch isreplaced with a new one, plasma concentrations initially decrease slowly for about 40 minutes onaverage, until absorption from the newly applied transdermal patch becomes faster than elimination,and plasma levels begin to rise again to reach a new peak at approximately 8 hours. At steady state,trough levels are approximately 50% of peak levels, in contrast to oral administration, with whichconcentrations fall off to virtually zero between doses. Although less pronounced than with the oralformulation, exposure to rivastigmine (Cmax and AUC) increased over-proportionally by a factor of 2.6and 4.9 when escalating from 4.6 mg/24 h to 9.5 mg/24 h and to 13.3 mg/24 h, respectively. Thefluctuation index (FI), a measure of the relative difference between peak and trough concentrations((Cmax-Cmin)/Cavg), was 0.58 for Exelon 4.6 mg/24 h transdermal patches, 0.77 for Exelon 9.5 mg/24 htransdermal patches and 0.72 for Exelon 13.3 mg/24 h transdermal patches, thus demonstrating amuch smaller fluctuation between trough and peak concentrations than for the oral formulation (FI =3.96 (6 mg/day) and 4.15 (12 mg/day)).

The dose of rivastigmine released from the transdermal patch over 24 hours (mg/24 h) cannot bedirectly equated to the amount (mg) of rivastigmine contained in a capsule with respect to plasmaconcentration produced over 24 hours.

The single-dose inter-subject variability in rivastigmine pharmacokinetic parameters (normalised todose/kg bodyweight) was 43% (Cmax) and 49% (AUC0-24h) after transdermal administration versus74% and 103%, respectively, after the oral form. The inter-patient variability in a steady-state study in

Alzheimer’s dementia was at most 45% (Cmax) and 43% (AUC0-24h) after use of the transdermal patch,and 71% and 73%, respectively, after administration of the oral form.

A relationship between active substance exposure at steady state (rivastigmine and metabolite

NAP226-90) and bodyweight was observed in Alzheimer’s dementia patients. Compared to a patientwith a body weight of 65 kg, the rivastigmine steady-state concentrations in a patient with a bodyweight of 35 kg would be approximately doubled, while for a patient with a body weight of 100 kg theconcentrations would be approximately halved. The effect of bodyweight on active substanceexposure suggests special attention to patients with very low body weight during up-titration (seesection 4.4).

Exposure (AUC∞) to rivastigmine (and metabolite NAP266-90) was highest when the transdermalpatch was applied to the upper back, chest, or upper arm and approximately 20-30% lower whenapplied to the abdomen or thigh.

There was no relevant accumulation of rivastigmine or the metabolite NAP226-90 in plasma in patientswith Alzheimer’s disease, except that plasma levels were higher on the second day of transdermal patchtherapy than on the first.

Rivastigmine is weakly bound to plasma proteins (approximately 40%). It readily crosses the blood-brainbarrier and has an apparent volume of distribution in the range of 1.8-2.7 l/kg.

Rivastigmine is rapidly and extensively metabolised with an apparent elimination half-life in plasma ofapproximately 3.4 hours after removal of the transdermal patch. Elimination was absorption rate limited(flip-flop kinetics), which explains the longer t½ after transdermal patch (3.4 h) versus oral or intravenousadministrations (1.4 to 1.7 h). Metabolism is primarily via cholinesterase-mediated hydrolysis to themetabolite NAP226-90. In vitro, this metabolite shows minimal inhibition of acetylcholinesterase(<10%).

Based on in vitro studies, no pharmacokinetic interaction is expected with medicinal productsmetabolised by the following cytochrome isoenzymes: 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 litres/h after a 0.2 mg intravenous dose and decreasedto 70 litres/h after a 2.7 mg intravenous dose, which is consistent with the non-linear, over-proportionalpharmacokinetics of rivastigmine due to saturation of its elimination.

The metabolite-to-parent AUC∞ ratio was around 0.7 after transdermal patch administration versus 3.5after oral administration, indicating that much less metabolism occurred after dermal compared to oraltreatment. Less NAP226-90 is formed following application of the transdermal patch, presumablybecause of the lack of presystemic (hepatic first pass) metabolism, in contrast to oral administration.

Unchanged rivastigmine is found in trace amounts in the urine; renal excretion of the metabolites is themajor route of elimination after transdermal patch administration. Following administration of oral 14C-rivastigmine, renal elimination was rapid and essentially complete (>90%) within 24 hours. Less than1% of the administered dose is excreted in the faeces.

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 for up to 12 mg/day.

Age had no impact on the exposure to rivastigmine in Alzheimer’s disease patients treated with Exelontransdermal patches.

No study was conducted with Exelon transdermal patches in subjects with hepatic impairment. After oraladministration, the Cmax of rivastigmine was approximately 60% higher and the AUC of rivastigmine wasmore than twice as high in subjects with mild to moderate hepatic impairment than in healthy subjects.

Following a single 3 mg or 6 mg oral dose, the mean oral clearance of rivastigmine was approximately46-63% lower in patients with mild to moderate hepatic impairment (n=10, Child-Pugh score 5-12,biopsy proven) than in healthy subjects (n=10).

No study was conducted with Exelon transdermal patches in subjects with renal impairment. Based onpopulation analysis, creatinine clearance did not show any clear effect on steady state concentrations ofrivastigmine or its metabolite. No dose adjustment is necessary in patients with renal impairment (seesection 4.2).

Oral and topical repeated-dose toxicity studies in mice, rats, rabbits, dogs and minipigs revealed onlyeffects associated with an exaggerated pharmacological action. No target organ toxicity was observed.

Oral and topical dosing in animal studies was limited 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 exceeding 104 times theforeseen clinical exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not show a genotoxic potential.

No evidence of carcinogenicity was found in oral and topical studies in mice and in an oral study inrats at the maximum tolerated dose. The exposure to rivastigmine and its metabolites wasapproximately equivalent to human exposure with highest doses of rivastigmine capsules andtransdermal patches.

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. Specific dermal studies inpregnant animals have not been conducted.

Rivastigmine transdermal patches were not phototoxic and considered to be a non-sensitiser. In someother dermal toxicity studies, a mild irritant effect on the skin of laboratory animals, including controls,was observed. This may indicate a potential for Exelon transdermal patches to induce mild erythema inpatients.

A mild eye/mucosal irritation potential of rivastigmine was identified in a rabbit study. Therefore, thepatient/caregiver should avoid contact with the eyes after handling of the patch (see section 4.4).

Backing layer

Polyethylene terephthalate film, lacquered

Medicinal product matrix:

Alpha-tocopherol

Poly(butylmethacrylate, methylmethacrylate)

Acrylic copolymer

Adhesive matrix

Alpha-tocopherol

Silicone oil

Dimethicone

Release liner

Polyester film, fluoropolymer-coated

To prevent interference with the adhesive properties of the transdermal patch, no cream, lotion orpowder should be applied to the skin area where the medicinal product is to be applied.

2 years

Do not store above 25°C.

Keep the transdermal patch in the sachet until use.

Exelon 9 mg/5 cm2, 18 mg/10 cm2 and 27 mg/15 cm2 transdermal patches are individually packaged inchild-resistant, heat-sealed sachets made of apaper/polyethyleneterephthalate/aluminum/polyacrylnitrile (PAN) multi-laminated material(paper/PET/alu/PAN) or in heat-sealed, child-resistant sachets made of multi-layer composite laminateconsisting of paper/polyethylene terephthalate/polyethylene/aluminum/polyamide(paper/PET/PE/alu/PA).

Exelon 4.6 mg/24 h transdermal patch

Available in packs containing 7, 30 or 42 sachets and in multipacks containing 60, 84 or 90 sachets.

Exelon 9.5 mg/24 h transdermal patch

Available in packs containing 7, 30 or 42 sachets and in multipacks containing 60, 84 or 90 sachets.

Exelon 13.3 mg/24 h transdermal patch

Available in packs containing 7 or 30 sachets and in multipacks containing 60 or 90 sachets.

Not all pack sizes may be marketed.

Used transdermal patches should be folded in half, with the adhesive side inwards, placed in the originalsachet and discarded safely and out of the reach and sight of children. Any used or unused transdermalpatches should be disposed of in accordance with local requirements or returned to the pharmacy.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

Exelon 4.6 mg/24 h transdermal patch

EU/1/98/066/019-022

EU/1/98/066/031-032

EU/1/98/066/035-038

EU/1/98/066/047-048

Exelon 9.5 mg/24 h transdermal patch

EU/1/98/066/023-026

EU/1/98/066/033-034

EU/1/98/066/039-042

EU/1/98/066/049-050

Exelon 13.3 mg/24 h transdermal patch

EU/1/98/066/027-030

EU/1/98/066/043-046

Date of first authorisation: 12 May 1998

Date of latest renewal: 20 May 2008

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

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