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• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.8 - Undesirable effects
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Section 4.4 - Add a paragraph on Bradycardia.

Section 4.8 - Add nightmares as a not known AE in psychiatric disorders.

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• Change to section 7 - Marketing authorisation holder
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Section 7 updated to change the address of the MAH from Horsham to Frimley.

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• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
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Section 4.5 - To update this section particularly in relation to Bradycardia.

Section 4.8 - Include information on Reporting of suspected adverse reactions.

Section 4.9 - Change the word Treatment to Management.

Section 5.2 - Include further information within Biotransformation and Elimination. Change the heading Elderly population to Older people.

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• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.6 - Fertility, pregnancy and lactation
• Change to section 4.8 - Undesirable effects
• Change to section 4.9 - Overdose
• Change to section 5.2 - Pharmacokinetic properties
• Change to section 5.3 - Preclinical safety data
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Section 4.2

Under Special populations, changes have been made to Hepatic and Renal impairment.

Section 4.4

In the paragraph above 'Other warnings and precautions' Include allergic dermatitis and delete skin hypersensitivity reactions.

Under Special populations, changes have been made to Hepatic impairment and Renal impairment has been deleted.

Section 4.6

To add the following sentence at the beginning of 'Pregnancy'

In pregnant animals, rivastigmine and/or metabolites crossed the placenta. It is not known if this occurs in humans.

To delete the sentence on Fertility and replace with:

No adverse effects of rivastmine were observed on fertility or reproductive preformance in rats (see section 5.3). Effects of rivastigmine on human fertility are not known.

Section 4.8

Within Tabulated list of adverse reactions change 854 to 1,670.

Include somnolence as a Not known AE under Nervous system disorders.

Under Skin and subcutaneous tissue disorders delete cutaneous hypersensitivity reactions.

General disorders and administration site conditions
	Common	Application site skin reactions (e.g. application site erythema*, application site pruritus*, application site oedema*, application site dermatitis, 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 oedema and application site pruritus were reported as “very common”.

Delete 'tremor' in second paragraph under 'Description of selected adverse reactions.

Delete current text of skin irritation and replace with:

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

 

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

Section 4.9

Information under 'Symptoms' has been updated.

Section 5.2

New paragraph above 'Renal impairment'.

Information on Renal impairment has changed.

Section 5.3

Rivastigmine was not mutagenic in a standard battery of in vitro and in vivo tests, except in a chromosomal aberration test in human peripheral lymphocytes at a dose exceeding 10⁴ times the foreseen clinical exposure. The in vivo micronucleus test was negative. The major metabolite NAP226-90 also did not show a genotoxic potential.

In animals, rivastigmine crosses the placenta and is excreted into milk. Oral studies in pregnant rats and rabbits gave no indication of teratogenic potential on the part of rivastigmine. In oral studies with male and female rats, no adverse effects of rivastigmine were observed on fertility or reproductive performance of either the parent generation or the offspring of the parents. Specific dermal studies in pregnant animals have not been conducted.

Rivastigmine transdermal patches were not phototoxic and considered to be a non-sensitiser. In some other 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 in patients.

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• Change to section 6.5 - Nature and contents of container
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Section 6.5

Addition of pack sizes of 42 and 84 for 4.6mg/24h and 9.5mg/24h patches.

Section 8

New EU numbers:

         EU/1/98/066/031-032 for 4.6mg / 24h patch.
EU/1/98/066/033-034 for 9.5mg / 24h patch.

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• Change to section 1 - Name of the medicinal product

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To remove the statement that 13.3mg is not currently marketed within section 1 of the SmPC.

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• Change to section 2 - Qualitative and quantitative composition
• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 4.6 - Fertility, pregnancy and lactation
• Change to section 4.7 - Effects on ability to drive and use machines
• Change to section 4.8 - Undesirable effects
• Change to section 5.1 - Pharmacodynamic properties
• Change to section 5.2 - Pharmacokinetic properties
• Change to section 6.5 - Nature and contents of container
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Section 2

For thea full list of excipients, see section 6.1.

Section 4.2

Posology

 

Transdermal patches	Rivastigmine in vivo release rates 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

 

Transdermal patches	Rivastigmine dose load	Rivastigmine in vivo release rates per 24 h
Exelon 4.6 mg/24 h	9 mg	4.6 mg
Exelon 9.5 mg/24 h	18 mg	9.5 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, this dose should be increased to 9.5 mg/24 h, which is the recommended effective dose.

 

Maintenance dose

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

 

Dose escalation

9.5 mg/24 h is the recommended daily maintenance effective dose which shouldcan be continued for as long as the patient continues to demonstrate is deriving therapeutic benefit. If well tolerated and only after a minimum of six months of treatment at 9.5 mg/24 h, the treating physician may consider increasing the dose to 13.3 mg/24 h in patients who have demonstrated a meaningful cognitive deterioration (e.g. decrease in the MMSE) and/or functional decline (based on physician judgement) while on the recommended daily effective 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 also be 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 until these adverse reactions resolve. Transdermal patch treatment can be resumed at the same dose if treatment is not interrupted for more than several three days. Otherwise treatment should be re-initiated with 4.6 mg/24 h.

As present

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

 

Special populations

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

·             Patients with body weight below 50 kg: Particular caution should be exercised in titrating patients 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 to discontinue due to adverse reactions.

·             Hepatic impairment: No dose adjustment is necessary for patients with hepatic impairment. However, due to increased exposure in these populations as observed with the oral forms, dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant hepatic impairment might experience more adverse reactions. Patients with severe hepatic impairment have not been studied (see sections 4.4 and 5.2).

·             Renal impairment: No dose adjustment is necessary for patients with renal impairment. However, due to increased exposure in these populations as observed with the oral forms, dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal impairment might experience more adverse reactions (see sections 4.4 and 5.2).

 

Method of administration

Transdermal patches should be applied once a day to clean, dry, hairless, intact healthy skin on the upper or lower back, upper arm or chest, in a place which will not be rubbed by tight clothing. It is not recommended to apply the transdermal patch to the thigh or to the abdomen due to decreased bioavailability 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 exact same 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 a time (see section 4.9).

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

·             If the patch falls off, a new one should be applied for the rest of the day, then it should be replaced at 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.

The transdermal patch should be pressed down firmly until the edges stick well. It can be used in everyday situations, including bathing and during hot weather.

 

The transdermal patch should be replaced by a new one after 24 hours. Only one transdermal patch should be worn at a time (see section 4.9). The transdermal patch should not be cut into pieces. Patients and caregivers should be instructed accordingly.

 

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

 

Paediatric population

The safety and efficacy of Exelon in children aged 0 to below 18 years have not been established. No data are available.

 

There is no relevant use of Exelon in the paediatric population in children aged 0 to below 18 years in the treatment of Alzheimer’s dementia.

Section 4.3

Only change:

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

Section 4.4

The incidence and severity of adverse reactions generally increase with increasing doses, particularly at dose changes. If treatment is interrupted for more than several three days, it should be re-initiated with 4.6 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 in serious adverse reactions; some cases have required hospitalisation, and rarely led to death (see section 4.9). Most cases of misuse of the medicinal product and dosing errors have involved not removing the old patch when putting on a new one and the use of multiple patches at the same time. Patients and their caregivers must be instructed on important administration instructions for Exelon transdermal patch (see section 4.2).

 

Gastrointestinal disorders

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

 

Weight loss

Patients with Alzheimer’s disease may lose weight whilst taking cholinesterase inhibitors, including rivastigmine. The patient’s weight should be monitored during therapy with Exelon transdermal patches.

 

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-ventricular block) (see section 4.8);

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

·             to patients predisposed to urinary obstruction and seizures because cholinomimetics may induce or 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 in intensity. Patients and caregivers should be instructed accordingly.

 

 These reactions are not in themselves an indication of sensitisation. However, use of rivastigmine patch may lead to allergic contact dermatitis.

 

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued (see section 4.3).

 

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

 

There have been rare post-marketing reports of patients experiencing disseminated skin hypersensitivity reactions 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.

 

Other warnings and precautions

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 if the eyes become red after handling the patch, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.

 

Special populations:

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

·             Hepatic impairment: Patients with clinically significant hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Consider using the 4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.

·             Renal impairment: Patients with clinically significant renal impairment might experience more adverse reactions (see sections 4.2 and 5.2). Consider using the 4.6 mg/24 h transdermal patch both as initial and maximum dose in these patients.

Section 4.5


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

Section 4.6

Pregnancy

No clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

 

Breast-feeding

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

 

Fertility

No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity.

Section 4.7

Alzheimer’s disease may cause gradual impairment of driving performance or compromise the ability to use machinerys. 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, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.

Section 4.8

Summary of the safety profile

The overall incidence of adverse events (AEs) in patients treated with Exelon 9.5 mg/24 h transdermal patches was lower than the rate in patients who received 3 to 12 mg/day Exelon capsule treatment (50.5% with Exelon 9.5 mg/24 h transdermal patches vs 63.3% with Exelon capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse reactions, including nausea and vomiting, were the most common adverse reactions in patients who received active treatment, and occurred at a substantially lower rate in the Exelon 9.5 mg/24 h transdermal patch group compared to the Exelon capsule group (7.2% vs 23.1% for nausea and 6.2% vs 17.0% for vomiting; 5.0% and 3.3% of patients on placebo reported nausea and vomiting, respectively).Application site skin reactions (usually mild to moderate application site erythema), are the most frequent adverse reactions observed with the use of Exelon transdermal patch. The next most common adverse reactions are gastrointestinal in nature including nausea and vomiting.

 

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

 

Tabulated list of adverse reactions

Table 1 displays the adverse reactions (events reasonably believed to be causally related to the medicinal product) reported in 854291 patients with Alzheimer’s dementia treated in randomised,a specific 24-week double-blind, placebo and active-controlled clinical studiesy with Exelon transdermal patches for a duration of 24‑48 weeks and from post-marketing dataat target dose of 9.5 mg/24 h (4.6 mg/24 h titrated to 9.5 mg/24 h).

 

Table 1

 

Infections and infestations
	Common	Urinary tract infection
Metabolism and nutrition disorders
	Common	Anorexia, decreased appetite
	UncommonNot known	Dehydration
Psychiatric disorders
	Common	Anxiety, depression, delirium, agitation
	Uncommon	Aggression
	Not known	Hallucinations, aggression, restlessness
Nervous system disorders
	Common	Headache, syncope, dizziness
	Uncommon	Psychomotor hyperactivity
	Very rare	Extrapyramidal symptoms
	Not known	Worsening of Parkinson’s disease, seizure
Cardiac disorders
	Uncommon	Bradycardia
	Not known	Atrioventricular block, atrial fibrillation, tachycardia, sick sinus syndrome
Vascular disorders
	Not known	Hypertension
Gastrointestinal disorders
	Common	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain
	Uncommon	Gastric ulcer
	Not known	Pancreatitis
Hepatobiliary disorders
	Not known	Hepatitis, elevated liver function tests
Skin and subcutaneous tissue disorders
	Common	Rash
	Not known	Pruritus, erythema, urticaria, vesicles, allergic dermatitis, disseminated cutaneous hypersensitivity reactions
Renal and urinary disorders
	Common	Urinary incontinence
General disorders and administration site conditions
	Common	Application site skin reactions (e.g. application site erythema, application site pruritus, application site oedema, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased
	RareNot known	Fall

 

Description of selected adverse reactions

When doses higher than 13.39.5 mg/24 h were used in the above-mentioned placebo-controlled study, dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure were observed more frequently than with 13.39.5 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 13.39.5 mg/24 h transdermal patches than with placebo.

 

Table 2 shows the most frequent adverse reactions reported during a 76-week period in an open-label clinical study conducted with Exelon transdermal patches in patients with dementia associated with Parkinson’s disease.

Table 2 deleted.

In patients with dementia associated with Parkinson’s disease, the following common adverse reactions have only been observed with Exelon capsules and not with Exelon transdermal patches: nausea, vomiting (very common); decreased appetite, restlessness, headache, worsening of Parkinson’s disease, bradycardia, diarrhoea, dyspepsia, salivary hypersecretion, sweating increased (common); dystonia, atrial fibrillation, atrioventricular block (uncommon).

 

The following adverse reactions have only been observed with Exelon capsules and oral solution and not in clinical studies with Exelon 9.5 mg/24 h transdermal patches: Dizziness (very common); agitation, somnolence, malaise, tremor, confusion, sweating increased (common); insomnia, accidental fall, elevated liver function tests (uncommon); seizures, duodenal ulcers, angina pectoris (rare); cardiac arrhythmia (e.g. atrio-ventricular block, atrial fibrillation and tachycardia), hypertension, pancreatitis, gastrointestinal haemorrhage, hallucination (very rare); and some cases of severe vomiting were associated with oesophageal rupture (not known).

 

Skin irritation

In a 24-week double-blind, placebo-controlled clinical trials, skin reactions were measured at each visit using a skin irritation rating scale that rated the degree of erythema, oedema, scaling, fissures, pruritus and pain/stinging/burning at the application site. The most commonly observed symptom was erythema which disappeared within 24 hours in the vast majority of patients. In thea 24-week double-blind study, the most commonly observed symptoms (skin irritation rating scale) with Exelon 9.5 mg/24 h transdermal patches were very slight (21.8%), mild (12.5%) or moderate (6.5%) erythema or very slight (11.9%), mild (7.3%) or moderate (5.0%) pruritus. The most commonly observed severe symptoms with Exelon 9.5 mg/24 h transdermal patches were pruritus (1.7%) and erythema (1.1%). Most skin reactions were limited to the application site and resulted in discontinuation in only 2.4% of the patients in the Exelon 9.5 mg/24 h transdermal patch group.

 

In a 48-week active-controlled clinical trial, cases of skin irritation were captured as patient or caregiver reported adverse reactions. The most commonly reported skin irritation events during the first 24 weeks of the double-blind period with Exelon 13.3 mg/24 h transdermal patches and Exelon 9.5 mg/24 h transdermal patches, respectively were application site erythema (5.7% vs 4.6%) and application site pruritus (3.6% vs 2.8%). The percentages decreased in both Exelon 13.3 mg/24 h transdermal patch and Exelon 9.5 mg/24 h transdermal patch treatment groups over time (>24 weeks): application site erythema (0.8% vs. 1.6%) and application site pruritus (0.4% vs. 1.2%), respectively. Application site pruritus led to discontinuation in 1.1% of the patients from each of the treatment groups during the total 48-week double-blind treatment phase. Application site reactions were mostly mild to moderate in severity and were rated as severe in less than 2% of patients.

 

A direct comparison of the rate of skin irritation events reported in each of these studies cannot be made due to the difference in data collection methods employed.

Section 5.1

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.

 

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 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 oral rivastigmine was similar to thate inhibition of AChE activity.

 

Clinical studies in Alzheimer’s dementia

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

 

24-week placebo-controlled study

 Patients involved in the placebo-controlledthis study had an MMSE (Mini-Mental State Examination) score of 10–20. Efficacy was established by the use of independent, domain-specific assessment tools which 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-based measure 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 physician incorporating 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 including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities related to finances). The 24-week results for the three assessment tools are summarised in Table 23.

Table 3 becomes Table 2, Table 4 becomes Table 3

48-week active comparator controlled study

Patients involved in the active comparator controlled study had an initial baseline MMSE score of 10‑24. The study was designed to compare the efficacy of the 13.3 mg/24 h transdermal patch against the 9.5 mg/24 h transdermal patch during a 48-week double-blind treatment phase in Alzheimer’s disease 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. Functional decline was assessed by the investigator and cognitive decline was defined as a decrease in the MMSE score of >2 points from the previous visit or a decrease of >3 points from baseline. Efficacy was established by the use of ADAS-Cog (Alzheimer’s Disease Assessment Scale – Cognitive subscale, a performance-based measure of cognition) and the ADCS-IADL (Alzheimer’s Disease Cooperative Study – Instrumental Activities of Daily Living) assessing instrumental activities which include maintaining finances, meal preparation, shopping, ability to orient oneself to surroundings, ability to be left unattended. The 48-week results for the two assessment tools are summarised in Table 4.

 

Table 4

 

Population/Visit			Exelon 15 cm2 N = 265		Exelon 10 cm2 N = 271		Exelon 15 cm2		Exelon 10 cm2
			n	Mean	n	Mean	DLSM	95% CI	p-value
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 Exelon 15 cm2 as compared to Exelon 10 cm2. ADCS-IADL scores: A positive difference in DLSM indicates greater improvement in Exelon 15 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) model adjusted for country and baseline ADAS-cog score. * p<0.05 Source: Study D2340‑Table 11-6 and Table 11-7

 

Section 5.2

Absorption

Absorption of rivastigmine from Exelon transdermal patches is slow. After the first dose, detectable plasma concentrations are observed after a lag time of 0.5‑1 hour. C_max is reached after 10‑16 hours. After the peak, plasma concentrations slowly decrease over the remainder of the 24-hour period of application. With multiple dosing (such as at steady state), after the previous transdermal patch is replaced with a new one, plasma concentrations initially decrease slowly for about 40 minutes on average, 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 which concentrations fall off to virtually zero between doses. Although less pronounced than with the oral formulation, exposure to rivastigmine (C_max and AUC) increased over-proportionally by a factor of 2.6 and 4.9 when escalating from 4.6 mg/24 h to 9.5 mg/24 h and to 13.3 mg/24 h, respectively. The fluctuation index (FI), a measure of the relative difference between peak and trough concentrations ((C_max-C_min)/C_avg), was 0.58 for Exelon 4.6 mg/24 h transdermal patches and, 0.77 for Exelon 9.5 mg/24 h transdermal patches and 0.72 for Exelon 13.3 mg/24 h transdermal patches, thus demonstrating a much smaller fluctuation between trough and peak concentrations than for the oral formulation (FI = 3.96 (6 mg/day) and 4.15 (12 mg/day)).

Titles changed as shown:

BiotranformationMetabolism

Paragraph below:

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

Elderly subjectspopulation

Subjects with hHepatic impairment

Subjects with rRenal impairment

Section 6.5

Primary packaging material

Each child-resistant sachet is made of a paper/polyester/aluminium/polyacrylonitrile multilaminated material. One sachet contains one transdermal patch.

 

Secondary packaging material

The sachets are packed in a carton.

Available in packs containing 7 or 30 sachets and in multipacks containing 60 (2x 30)  or 90 (3x 30) sachets.


At the end of SPC:

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

 

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.3 - Contraindications
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.8 - Undesirable Effects
• Change to section 5.1 - Pharmacodynamic Properties

Date of revision of text on the SPC: 20-Apr-2012

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Updates to sections 4.2, 4.3, 4.4, 4.8 and 5.1 as shown below:

4.2       Posology and method of administration

 

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

 

 

 

 

 

Posology

 

Transdermal patches	Rivastigmine	Rivastigmine in
	dose load	vivo release rates
		per 24 h
Exelon 4.6 mg/24 h	9 mg	4.6 mg
Exelon 9.5 mg/24 h	18 mg	9.5 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, this dose should be increased to 9.5 mg/24 h, which is the recommended effective dose.

Maintenance dose

9.5 mg/24 h is the recommended daily maintenance dose which can be continued for as long as the patient is deriving therapeutic benefit. Treatment should be temporarily interrupted if gastrointestinal adverse reactions are observed until these adverse reactions resolve. Transdermal patch treatment can be resumed at the same dose if treatment is not interrupted for more than several days. Otherwise treatment should be re-initiated with 4.6 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), patients treated with Exelon capsules or oral solution can be switched to Exelon transdermal patches as follows:

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

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

·         A patient on a stable and well tolerated dose of 9 mg/day oral rivastigmine can be switched to 9.5 mg/24 h transdermal patches. If the oral dose of 9 mg/day has not been stable and well tolerated, 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 transdermal patches.

 

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

 

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

 

Method of administration

Transdermal patches should be applied once a day to clean, dry, hairless, intact healthy skin on the upper or lower back, upper arm or chest, in a place which will not be rubbed by tight clothing. It is not recommended to apply the transdermal patch to the thigh or to the abdomen due to decreased bioavailability 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 exact same skin location within 14 days should be avoided to minimise the potential risk of skin irritation.

 

The transdermal patch should be pressed down firmly until the edges stick well. It can be used in everyday situations, including bathing and during hot weather.

 

The transdermal patch should be replaced by a new one after 24 hours. Only one transdermal patch should be worn at a time (see section 4.9). The transdermal patch should not be cut into pieces. Patients and caregivers should be instructed accordingly.

 

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

 

Paediatric population

The safety and efficacy of Exelon in children aged 0 to below 18 years have not been established. No data are available.

 

There is no relevant use of Exelon in the paediatric population in children aged 0 to below 18 years in the treatment of Alzheimer’s dementia.

Children and adolescents (age below 18 years): Rivastigmine is not recommended for use in children and adolescents.

 

4.3       Contraindications

 

The use of this medicinal product is contraindicated in patients with known Hhypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1 used in the formulation.

 

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

 

 

4.4       Special warnings and precautions for use

 

The incidence and severity of adverse reactions generally increase with increasing doses, particularly at dose changes. If treatment is interrupted for more than several days, it should be re-initiated with 4.6 mg/24 h.

 

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

 

Patients with Alzheimer’s disease may lose weight whilst taking cholinesterase inhibitors, including rivastigmine. The patient’s weight should be monitored during therapy with Exelon transdermal patches.

 

Care must be taken when prescribing Exelon transdermal patches:

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

·         to patients with active gastric or duodenal ulcers or patients predisposed to these conditions because rivastigmine may cause increased gastric secretions (see section 4.8)

·         to patients predisposed to urinary obstruction and seizures because cholinomimetics may induce or exacerbate these diseases.

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

 

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

 

Allergic contact dermatitis should be suspected if application site reactions spread beyond the patch size, if there is evidence of a more intense local reaction (e.g. increasing erythema, oedema, papules, vesicles) and if symptoms do not significantly improve within 48 hours after patch removal. In these cases, treatment should be discontinued (see section 4.3).

 

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

 

There have been rare post-marketing reports of patients experiencing disseminated skin hypersensitivity reactions 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.

 

Rivastigmine may exacerbate or induce extrapyramidal symptoms.

 

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

 

Special populations:

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

·         Hepatic impairment: Patients with clinically significant hepatic impairment might experience more adverse reactions (see section 5.2).

 

 

4.8       Undesirable effects

 

The overall incidence of adverse events (AEs) in patients treated with Exelon 9.5 mg/24 h transdermal patches was lower than the rate in patients who received 3 to 12 mg/day Exelon capsule treatment (50.5% with Exelon 9.5 mg/24 h transdermal patches vs 63.3% with Exelon capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse reactions, including nausea and vomiting, were the most common adverse reactions in patients who received active treatment, and occurred at a substantially lower rate in the Exelon 9.5 mg/24 h transdermal patch group compared to the Exelon capsule group (7.2% vs 23.1% for nausea and 6.2% vs 17.0% for vomiting; 5.0% and 3.3% of patients on placebo reported nausea and vomiting, respectively).

 

Table 1 displays the adverse reactions (events reasonably believed to be causally related to the medicinal product) reported in 291 patients with Alzheimer’s dementia treated in a specific 24-week double-blind, placebo and active-controlled clinical study with Exelon transdermal patches at target dose of 9.5 mg/24 h (4.6 mg/24 h titrated to 9.5 mg/24 h).

 

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

 

Table 1 displays the adverse reactions (events reasonably believed to be causally related to the medicinal product) reported in 291 patients with Alzheimer’s dementia treated in a specific 24-week double-blind, placebo and active-controlled clinical study with Exelon transdermal patches at target dose of 9.5 mg/24 h (4.6 mg/24 h titrated to 9.5 mg/24 h).

 

Table 1

Infections and infestations
	Common	Urinary tract infection
Metabolism and nutrition disorders
	Common Not known	Anorexia Dehydration
Psychiatric disorders
	Common	Anxiety, depression, delirium
	Not known	Hallucinations, aggression, restlessness
Nervous system disorders
	Common	Headache, syncope
	Very rare	Extrapyramidal symptoms
	Not known	Worsening of Parkinson’s disease, seizure
Cardiac disorders
	Uncommon	Bradycardia
	Not known	Atrioventricular block, atrial fibrillation, tachycardia, sick sinus syndrome
Vascular disorders
	Not known	Hypertension
Gastrointestinal disorders
	Common	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain
	Uncommon	Gastric ulcer
	Not known	Pancreatitis
Hepatobiliary disorders
	Not known	Hepatitis, elevated liver function tests
Skin and subcutaneous tissue disorders
	Common	Rash
	Not known	Pruritus, erythema, urticaria, vesicles, allergic dermatitis
General disorders and administration site conditions
	Common	Application site skin reactions (e.g. application site erythema, application site pruritus, application site oedema, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased
	Not known	Fall

When doses higher than 9.5 mg/24 h were used in the above-mentioned study, dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure were observed more frequently than with 9.5 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 9.5 mg/24 h transdermal patches than with placebo.

 

Table 2 shows the most frequent adverse reactions reported during a 76-week period in an open-label clinical study conducted with Exelon transdermal patches in patients with dementia associated with Parkinson’s disease.

 

Table 2

 

Metabolism and nutrition disorders
Common	Dehydration
Psychiatric disorders
Common	Insomnia
Common	Anxiety
Common	Agitation
Common	Hallucination, visual
Common	Depression
Common	Aggression
Nervous system disorders
Common	Headache
Common	Tremor
Common	Dizziness
Common	Somnolence
Common	Bradykinesia
Common	Dyskinesia
Common	Hypokinesia
Common	Cogwheel rigidity
Common	Weight decrease
Vascular disorders
Common	Hypertension
Gastrointestinal disorders
Common	Abdominal pain
General disorders and administration site conditions
Very common	Fall
Very common	Application site erythema
Common	Application site irritation, pruritus, rash
Common	Fatigue
Common	Asthenia
Common	Gait disturbance

 

In patients with dementia associated with Parkinson’s disease, the following common adverse reactions have only been observed with Exelon capsules and not with Exelon transdermal patches: nausea, vomiting (very common);decreased appetite, restlesness, headache, worsening of Parkinson’s disease, bradycardia, diarrhoea, dyspepsia, salivary hypersecretion, sweating increased (common); dystonia, atrial fibrillation, atrioventricular block (uncommon).

 

The following adverse reactions have only been observed with Exelon capsules and oral solution and not in clinical studies with Exelon 9.5 mg/24 h transdermal patches: Dizziness (very common); agitation, somnolence, malaise, tremor, confusion, sweating increased (common); insomnia, accidental fall, elevated liver function tests (uncommon); seizures, duodenal ulcers, angina pectoris (rare); cardiac arrhythmia (e.g. atrio-ventricular block, atrial fibrillation and tachycardia), hypertension, pancreatitis, gastrointestinal haemorrhage, hallucination (very rare); and some cases of severe vomiting were associated with oesophageal rupture (not known).

 

Skin irritation

In clinical trials, skin reactions were measured at each visit using a skin irritation rating scale that rated the degree of erythema, oedema, scaling, fissures, pruritus and pain/stinging/burning at the application site. The most commonly observed symptom was erythema which disappeared within 24 hours in the vast majority of patients. In a 24-week double-blind study, the most commonly observed symptoms (skin irritation rating scale) with Exelon 9.5 mg/24 h transdermal patches were very slight (21.8%), mild (12.5%) or moderate (6.5%) erythema or very slight (11.9%), mild (7.3%) or moderate (5.0%) pruritus. The most commonly observed severe symptoms with Exelon 9.5 mg/24 h transdermal patches were pruritus (1.7%) and erythema (1.1%). Most skin reactions were limited to the application site and resulted in discontinuation in only 2.4% of the patients in the Exelon 9.5 mg/24 h transdermal patch group.

 

5.1       Pharmacodynamic properties

 

Pharmacotherapeutic group: 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.

 

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 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 oral rivastigmine was similar to that of AChE.

 

Clinical studies in Alzheimer’s dementia

The efficacy of Exelon transdermal patches in patients with Alzheimer’s dementia has been demonstrated in a 24-week double-blind core study and its open-label extension phase. Patients involved in this study had an MMSE (Mini-Mental State Examination) score of 10–20. Efficacy was established by the use of independent, domain-specific assessment tools which 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-based measure 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 physician incorporating 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 including personal hygiene, feeding, dressing, household chores such as shopping, retention of ability to orient oneself to surroundings as well as involvement in activities related to finances). The 24-week results for the three assessment tools are summarised in Table 32.

 

Table 23

	Exelon	Exelon	Placebo
ITT-LOCF population	transdermal patches 9.5 mg/24 h N = 251	capsules 12 mg/day 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 p-value versus placebo	-0.6 ± 6.4 0.005*1	-0.6 ± 6.2  0.003*1	1.0 ± 6.8
ADCS-CGIC
	(n=248)	(n=253)	(n=278)
Mean score ± SD	3.9 ± 1.20	3.9 ± 1.25	4.2 ± 1.26
p-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 p-value versus placebo	-0.1 ± 9.1 0.013*1	-0.5 ± 9.5  0.039*1	-2.3 ± 9.4

* p≤0.05 versus placebo

ITT: Intent-To-Treat; LOCF: Last Observation Carried Forward

¹Based on ANCOVA with treatment and country as factors and baseline value as a covariate. Negative ADAS-Cog changes indicate improvement. Positive ADCS-ADL changes indicate improvement.

²Based on CMH test (van Elteren test) blocking for country. ADCS-CGIC scores <4 indicate improvement.

 

The results for clinically relevant responders from the 24-week study are provided in Table 34. Clinically relevant improvement was defined a priori as at least 4-point improvement on the ADAS-Cog, no worsening on the ADCS-CGIC, and no worsening on the ADCS-ADL.

 

Table 34

	Patients with clinically significant response (%)
	Exelon	Exelon	Placebo
ITT-LOCF population	transdermal patches 9.5 mg/24 h N = 251	capsules 12 mg/day N = 256	N = 282
At least 4 points	17.4	19.0	10.5
improvement on ADAS-Cog
with no worsening on ADCS­-
CGIC and ADCS-ADL
p-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 exposure similar to that provided by an oral dose of 12 mg/day.

 

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 section 4.2 for information on paediatric use).

 

 

 

Reasons for adding or updating:

• Change to section 4.8 - Undesirable Effects
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 20-Oct-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.8.

'elevated liver function tests' has been added as not known within Hepatobilary disorders in Table 1 of Section 4.8.

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.8 - Undesirable Effects
• Change to section 10 date of revision of the text

Date of revision of text on the SPC: 23-May-2011

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Section 4.4

Second paragraph changed as below:

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

Section 4.8

As present........

Table 1 

Infections and infestations
	Common:	Urinary tract infection
Metabolism and nutrition disorders
	Common:	Anorexia
	Not known	Dehydration
Psychiatric disorders
	Common:	Anxiety, depression, delirium
	Not known:	Hallucinations, aggression, restlessness
Nervous system disorders
	Common:	Headache, syncope
	Very rare:	Extrapyramidal symptoms
	Not known	Worsening of Parkinson’s disease, seizure
Cardiac disorders
	Uncommon:	Bradycardia
	Not known	Atrioventricular block, atrial fibrillation, tachycardia, sick sinus syndrome
Vascular disorders
	Not known	Hypertension
Gastrointestinal disorders
	Common:	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain
	Uncommon:	Gastric ulcer
	Not known	Pancreatitis
Hepatobiliary disorders
	Not known	Hepatitis
Skin and subcutaneous tissue disorders
	Common:	Rash
	Not known	Pruritus, erythema, urticaria, vesicles, allergic dermatitis
General disorders and administration site conditions
	Common:	Application site skin reactions (e.g. application site erythema, application site pruritus, application site oedema, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased
	Not known	Fall

 

When doses higher than 9.5 mg/24 h were used in the above-mentioned study, dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure were observed more frequently than with 9.5 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 9.5 mg/24 h transdermal patches than with placebo.

 

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

 

Nervous system disorders
	Not known:	Worsening of Parkinson’s disease, seizure
Cardiac disorders
	Not known:	Atrioventricular block, atrial fibrillation, tachycardia
Vascular disorders
	Not known:	Hypertension
Gastrointestinal disorders
	Not known:	Pancreatitis
Skin and subcutaneous tissue disorders
	Not known:	Pruritus, rash, erythema, urticaria, vesicles, allergic dermatitis
General disorders and administration site conditions
	Not known:	Fall, application site reaction (such as erythema, pruritus, irritation, rash, vesicles)

 

Reasons for adding or updating:

• Change to section 4.8 - Undesirable Effects
• Change to section 4.9 - Overdose
• Change to section 10 date of revision of the text
• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.2 - Posology and method of administration

Date of revision of text on the SPC: 27-Apr-2010

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Update to Section 4.2, 4.6, 4.8, 4.9 and 10 as follows:

Section 4.2 the following paragraph has been amended:

The transdermal patch should be replaced by a new one after 24 hours. Only one transdermal patch should be worn at a time (see section 4.9). The transdermal patch should not be cut into pieces. Patients and caregivers should be instructed accordingly.

Section 4.6 title has been amended:

 

4.6     Fertility, pPregnancy and lactation

 

No clinical data on exposed pregnancies are available. No effects on fertility or embryofoetal development were observed in rats and rabbits, except at doses related to maternal toxicity. In peri/postnatal studies in rats, an increased gestation time was observed. Rivastigmine should not be used during pregnancy unless clearly necessary.

 

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

Section 4.8 changes as follows:

4.8    Undesirable effects

 

The overall incidence of adverse events (AEs) in patients treated with Exelon 9.5 mg/24 h transdermal patches was lower than the rate in patients who received 3 to 12 mg/day Exelon capsule treatment (50.5% with Exelon 9.5 mg/24 h transdermal patches vs 63.3% with Exelon capsules; 46.0% of patients on placebo reported AEs). Gastrointestinal adverse reactions, including nausea and vomiting, were the most common adverse reactions in patients who received active treatment, and occurred at a substantially lower rate in the Exelon 9.5 mg/24 h transdermal patch group compared to the Exelon capsule group (7.2% vs 23.1% for nausea and 6.2% vs 17.0% for vomiting; 5.0% and 3.3% of patients on placebo reported nausea and vomiting, respectively).

 

Table 1 displays the adverse reactions (events reasonably believed to be causally related to the medicinal product) reported in 291 patients with Alzheimer’s dementia treated in a specific 24-week double-blind, placebo and active-controlled clinical study with Exelon transdermal patches at target dose of 9.5 mg/24 h (4.6 mg/24 h titrated to 9.5 mg/24 h).

 

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

 

Table 1

 

Infections and infestations
	Common:	Urinary tract infection
Metabolism and nutrition disorders
	Common:	Anorexia
Psychiatric disorders
	Common:	Anxiety, depression, delirium
	Not known:	Hallucinations
Nervous system disorders
	Common:	Headache, syncope
	Very rare:	Extrapyramidal symptoms
Cardiac disorders
	Uncommon:	Bradycardia
Gastrointestinal disorders
	Common:	Nausea, vomiting, diarrhoea, dyspepsia, abdominal pain
	Uncommon:	Gastric ulcer
Skin and subcutaneous tissue disorders
	Common:	Rash
General disorders and administration site conditions
	Common:	Application site skin reactions (e.g. application site erythema, application site pruritus, application site oedema, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased

 

When doses higher than 9.5 mg/24 h were used in the above-mentioned study, dizziness, insomnia, agitation, decreased appetite, atrial fibrillation and cardiac failure were observed more frequently than with 9.5 mg/24 h or placebo, suggesting a dose effect relationship. However, these events did not occur at a higher frequency with Exelon 9.5 mg/24 h transdermal patches than with placebo.

 

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

 

Nervous system disorders
	Not known:	Worsening of Parkinson’s disease, seizure
Cardiac disorders
	Not known:	Atrioventricular block, atrial fibrillation, tachycardia
Vascular disorders
	Not known:	Hypertension
Gastrointestinal disorders
	Not known:	Pancreatitis
Skin and subcutaneous tissue disorders
	Not known:	Pruritus, rash, erythema, urticaria, vesicles, allergic dermatitis
General disorders and administration site conditions
	Not known:	Fall, application site reaction (such as erythema, pruritus, irritation, rash, vesicles)

 

The following adverse reactions have only been observed with Exelon capsules and oral solution and not in clinical studies with Exelon 9.5 mg/24 h transdermal patches: Dizziness (very common); agitation, somnolence, malaise, tremor, confusion, sweating increased (common); insomnia, accidental fall, elevated liver function tests (uncommon); seizures, duodenal ulcers, angina pectoris (rare); cardiac arrhythmia (e.g. atrio-ventricular block, atrial fibrillation and tachycardia), hypertension, pancreatitis, gastrointestinal haemorrhage, hallucination (very rare); and some cases of severe vomiting were associated with oesophageal rupture (not unknown).

 

Skin irritation

In clinical trials, skin reactions were measured at each visit using a skin irritation rating scale that rated the degree of erythema, oedema, scaling, fissures, pruritus and pain/stinging/burning at the application site. The most commonly observed symptom was erythema which disappeared within 24 hours in the vast majority of patients. In a 24-week double-blind study, the most commonly observed symptoms (skin irritation rating scale) with Exelon 9.5 mg/24 h transdermal patches were very slight (21.8%), mild (12.5%) or moderate (6.5%) erythema or very slight (11.9%), mild (7.3%) or moderate (5.0%) pruritus. The most commonly observed severe symptoms with Exelon 9.5 mg/24 h transdermal patches were pruritus (1.7%) and erythema (1.1%). Most skin reactions were limited to the application site and resulted in discontinuation in only 2.4% of the patients in the Exelon 9.5 mg/24 h transdermal patch group.

 

Section 4.9 changes to the first paragraph as follows:

4.9     Overdose

 

Symptoms

Most cases of accidental overdose of oral rivastigmine 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 and diarrhoea, hypertension or hallucinations. Due to the known vagotonic effect of cholinesterase inhibitors on heart rate, bradycardia and/or syncope may also occur. Ingestion of 46 mg of oral rivastigmine occurred in one case; following conservative management the patient fully recovered within 24 hours. There are currently no data on overdose with Exelon transdermal patches.Overdose with Exelon transdermal patch resulting from misuse/dosing errors (application of multiple patches at a time) has been reported in the post-marketing setting. The typical symptoms reported among these cases are similar to those seen with cases of overdose associated with Exelon oral formulations.

 

Section 10 changes as follows:

10.     DATE OF REVISION OF THE TEXT

 

27-04-2010

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu

 

Reasons for adding or updating:

• Change to section 10 date of revision of the text
• Removal of Black Triangle

Date of revision of text on the SPC: 06-Nov-2009

Legal Category:POM

Black Triangle (CHM): NO

Free-text change information supplied by the pharmaceutical company:

Removal of the black triangle and update to date of revision of the text.

Reasons for adding or updating:

• Change to section 4.6 - Pregnancy and Lactation
• Change to section 4.4 - Special warnings and precautions for Use
• Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
• Change to section 4.7 - Effects on Ability to Drive and Use Machines
• Change to section 4.8 - Undesirable Effects

Date of revision of text on the SPC: 20-May-2008

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:



SECTION 4.4:

 

·        “As with other cholinergic substances” has been deleted.

 

SECTION 4.5:

 

·        “Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.”

 

has been added.

 

SECTION 4.6:

 

·        The separate subheadings “Pregnancy” and “Lactation” have been deleted.

 

SECTION 4.7:

 

·        “As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines.”

 

has been added.

 

SECTION 4.8:

 

·   “Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000) and not known (cannot be estimated from the available data).”

 

            Moved to before table 1, as opposed to after the table.

 

  

 

Reasons for adding or updating:

• New SPC for new product