4.1. Therapeutic indications

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

4.2. Posology and method of administration

Zeyzelf® twice weekly transdermal patches should be applied twice weekly on fixed days (after four and three days, respectively) (please see also 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 in vivo release rates per 24 h

Zeyzelf® twice weekly 4.6 mg/24 h

4.6 mg

Zeyzelf® twice weekly 9.5 mg/24 h

9.5 mg

Initial dose

Treatment is started with 4.6 mg/24 h.

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 effective dose which should be continued for as long as the patient continues to demonstrate 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 13.3 mg/24 h dose strength cannot be achieved with Zeyzelf® twice weekly. For conditions where this strength should be used, other rivastigmine containing transdermal patches of the 13.3 mg/24 h strength are available.

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 three 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 rivastigmine capsules or oral solution can be switched to Zeyzelf® twice weekly 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.

Special populations

• Paediatric population: There is no relevant use of rivastigmine 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: Due to increased exposure in mild to moderate hepatic impairment as observed with the oral formulation, dosing recommendations to titrate according to individual tolerability should be closely followed. Patients with clinically significant hepatic impairment may experience more dose-dependent adverse reactions. Patients with severe hepatic impairment have not been studied. Particular caution should be exercised in titrating these patients (see sections 4.4 and 5.2).

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

Method of administration

Zeyzelf® twice weekly is for transdermal use.

Transdermal patches should be applied twice weekly on fixed days (after four and three days, respectively) 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.

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.

Patients and caregivers should be instructed on important administration instructions:

• The pack contains for each application a rectangular, translucent transdermal patch and an oval, beige adhesive cover.

Both patches are individually sealed in sachets. The adhesive cover is exclusively used for fixation of the transdermal patch.

• The previous patch must be removed before applying a new one (see section 4.9).

• The patch should be replaced by a new one latest after 4 days. Only one patch should be worn at a time (see section 4.9).

• The patch should be pressed down firmly for approx. 15 seconds using the palm of the hand until the edges stick well. Then it is covered with the adhesive cover and pressed down firmly for at least 30 seconds using the palm of the hand until it sticks well.

• If the patch falls off, a new one should be applied and be replaced at the same time as usual.

• 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 transdermal patch as well as the adhesive cover should not be cut into pieces.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Zeyzelf® twice weekly transdermal patches are multiday patches. Care should be exercised and application of more than one patch at the same time should be avoided.

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 resulting in overdose

Misuse of the medicinal product and dosing errors with rivastigmine 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 rivastigmine 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 rivastigmine transdermal patches.

Bradycardia

Electrocardiogram QT prolongation may occur in patients treated with certain cholinesterase inhibitor products including rivastigmine. Rivastigmine may cause bradycardia which constitutes a risk factor in the occurrence of torsade de pointes, predominantly in patients with risk factors. Caution is advised in patients with pre-existing, or a family history of, QTc prolongation or 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. Clinical monitoring (ECG) may also be required (see sections 4.5 and 4.8).

Other adverse reactions

Care must be taken when prescribing Zeyzelf® twice weekly 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 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).

Other warnings and precautions

Rivastigmine may exacerbate or induce extrapyramidal symptoms.

Contact with the eyes should be avoided after handling Zeyzelf® twice weekly 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 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).

4.5. Interaction with other medicinal products and other forms of interaction

No specific interaction studies have been performed with rivastigmine 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 betablockers 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 QT prolongation- or 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast feeding

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.

Fertility

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.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

Application site skin reactions (usually mild to moderate application site erythema), are the most frequent adverse reactions observed with the use of rivastigmine 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).

Tabulated list of adverse reactions

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 rivastigmine transdermal patches for a duration of 24-48 weeks and from post-marketing data.

Table 1

Infections and infestations

Common

Urinary tract infection

Metabolism and nutrition disorders

Common

Anorexia, decreased appetite

Uncommon

Dehydration

Psychiatric disorders

Common

Anxiety, depression, delirium, agitation

Uncommon

Aggression

Not known

Hallucinations, restlessness, nightmares

Nervous system disorders

Common

Headache, syncope, dizziness

Uncommon

Psychomotor hyperactivity

Very rare

Extrapyramidal symptoms

Not known

Worsening of Parkinson’s disease, seizure, tremor, somnolence, Pleurothotonus (Pisa syndrome)

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)

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

Rare

Fall

Description of selected adverse reactions

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

The following adverse reactions have only been observed with rivastigmine capsules and oral solution and not in clinical studies with rivastigmine 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).

Skin irritation

In a comparative bioavailability study performed with multiple patch applications (over a period of 11 days) to 58 healthy male subjects aged between 18 and 50 years, most of the observed application site reactions were rated with score 1 (“minimal erythema, barely perceptible”) and score 2 (“definite erythema, readily visible; minimal oedema or minimal papular response”) according to the classification suggested by the EMA guideline (EMA/CPMP/EWP/280/96 Corr1). In very few cases score 3 (“erythema and papules”) was assigned. In one single case application site erosion was observed shortly after removal of the last out of three patches. This application site reaction was only mild in intensity and resolved spontaneously in the evening of the same day. None of the observed application site reactions led to discontinuation or required any treatment. All application site reactions improved over time within the observation period of 48 hours following removal of the patch.

In another adhesion and skin irritation clinical trial performed with a single patch application in elderly subject population (48 subjects aged between 55 and 90), application site reactions were mostly mild in intensity. Erythema was the most frequently observed dermal response. In general, observed application site reactions showed an improvement within the observation time interval of 72 hours following removal of the patch.

For 6 subjects (12.50%), a vesicular reaction [score 6 according to the classification suggested by the EMA guideline (EMA/CPMP/EWP/280/96 Corr1) and score 5 according to the Questions & Answers document (published in June 2018)] was seen after patch removal. In all cases, the reaction was of mild intensity and resolved spontaneously within a short period of time following patch removal (few hours to few days).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 24 hours after the overdose.

Cholinergic toxicity has been reported with muscarinic symptoms that are observed with moderate poisonings such as miosis, flushing, digestive disorders including abdominal pain, nausea, vomiting and diarrhoea, bradycardia, bronchospasm and increased bronchial secretions, hyperhidrosis, involuntary urination and/or defecation, lacrimation, hypotension and salivary hypersecretion.

In more severe cases nicotinic effects might develop such as muscular weakness, fasciculations, seizures and respiratory arrest with possible fatal outcome.

Additionally there have been post-marketing cases of dizziness, tremor, headache, somnolence, confusional state, hypertension, hallucinations and malaise. Overdose with rivastigmine transdermal patch resulting from misuse/dosing errors (application of multiple patches at a time) has been reported in the post-marketing setting and rarely in clinical trials.

Management

As rivastigmine has a plasma half-life of about 3.4 hours and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose all Zeyzelf® twice weekly transdermal patches should be removed immediately and no further transdermal patch should be applied for the next 24 hours. In overdose accompanied by severe nausea and vomiting, the use of antiemetics should be considered. Symptomatic treatment for other adverse reactions should be given as necessary.

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