Novartis Pharmaceuticals UK Ltd

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

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

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

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

* 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

*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).

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.

Table 1 

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.

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

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.

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

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.