Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Hypersensitivity to the active substance rivastigmine, to other carbamate derivatives or to any of the excipients listed in section 6.1.
Previous history of application site reactions suggestive of allergic contact dermatitis with rivastigmine patch (see 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 three days, it should be re-initiated with 4.6 mg/24 h.
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 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.
Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de pointes, predominantly in patients with risk factors. Caution is advised in patients at higher risk of developing torsade de pointes; for example, those with uncompensated heart failure, recent myocardial infarction, bradyarrhythmias, a predisposition to hypokalaemia or hypomagnesaemia, or concomitant use with medicinal products known to induce QT prolongation and/or torsade de pointes (see sections 4.5 and 4.8).
Care must be taken when prescribing Exelon transdermal patches:
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 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 if the eyes become red after handling the patch, rinse immediately with plenty of water and seek medical advice if symptoms do not resolve.
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.
Patients with clinically significant hepatic impairment may experience more adverse reactions. Dosing recommendations to titrate according to individual tolerability must 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 muscle relaxants during anaesthesia. Caution is recommended when selecting anaesthetic agents. Possible dose adjustments or temporarily stopping treatment can be considered if needed.
In view of its pharmacodynamic effects and possible additive effects, rivastigmine should not be given concomitantly with other cholinomimetic substances. Rivastigmine might interfere with the activity of anticholinergic medicinal products (e.g. oxybutynin, tolterodine).
Additive effects leading to bradycardia (which may result in syncope) have been reported with the combined use of various beta-blockers (including atenolol) and rivastigmine. Cardiovascular beta- blockers are expected to be associated with the greatest risk, but reports have also been received in patients using other beta-blockers. Therefore, caution should be exercised when rivastigmine is combined 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 of rivastigmine with torsades de pointes-inducing medicinal products such as antipsychotics 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 moxifloxacine should 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 by warfarin is not affected by administration of oral rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and oral rivastigmine.
Concomitant administration of rivastigmine with commonly prescribed medicinal products, such as antacids, 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 rivastigmine or 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 occurs in humans. No clinical data on exposed pregnancies are available. 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 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 (see section 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 to use 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, in patients with dementia treated with rivastigmine, the ability to continue driving or operating complex machines should be routinely evaluated by the treating physician.
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 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 reported in 1,670 patients with Alzheimer’s dementia treated in randomised, double-blind, placebo and active-controlled clinical studies with Exelon transdermal patches 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
Uncommon: Bradycardia
Not known: Atrioventricular block, atrial fibrillation, tachycardia, sick sinus syndrome
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 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”.
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 not in clinical studies with Exelon transdermal patches: malaise, confusion, sweating increased (common); duodenal ulcers, angina pectoris (rare); gastrointestinal haemorrhage (very rare); and some cases of severe vomiting were associated with oesophageal rupture (not known).
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 treated with Exelon transdermal patches in a Japanese study.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
To prevent interference with the adhesive properties of the transdermal patch, no cream, lotion or powder should be applied to the skin area where the medicinal product is to be applied.
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