4.1. Therapeutic indications

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

Voleze 4.6 mg/24 h transdermal patch is indicated in adults.

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 in vivo

release rates per 24 h

Voleze 4.6 mg/24 h

4.6 mg

Voleze 9.5 mg/24 h

9.5 mg

Voleze 13.3 mg/24 h

13.3 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, this dose 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 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 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 capsules or oral solutions containing rivastigmine can be switched to Voleze 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

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).

Paediatric population

There is no relevant use of Voleze 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 increased exposure in these populations as observed with the oral forms, dosing recommendations to titrate accordingly 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).

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.

4.3. Contraindications

Hypersensitivity to the active substance, 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

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.

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)

Misuse of the medicinal product and dosing errors resulting in overdose

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

Other adverse reactions

Care must be taken when prescribing Voleze 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).

Other warnings and precautions

Rivastigmine may exacerbate or induce extrapyramidal symptoms.

Contact with the eyes should be avoided after handling Voleze 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.

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

No 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, rivastigmine should not be given concomitantly with other cholinomimetic substances and might interfere with the activity of anticholinergic medicinal products.

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, beta blockers, 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:

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 into milk. It is not known if rivastigmine is excreted into human milk. Therefore, women on rivastigmine should not breastfeed.

Fertility:

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

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 machinery. 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 854 patients with Alzheimer's dementia treated in randomised, double-blind, placebo and active-controlled clinical studies with rivastigmine transdermal patches or 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, 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 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

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 Voleze13.3 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: somnolence, malaise, tremor, 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 24-week double-blind, placebo-controlled clinical trial, 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 rivastigmine 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 rivastigmine 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 rivastigmine 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 rivastigmine 13.3 mg/24 h transdermal patches and rivastigmine 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 rivastigmine 13.3 mg/24 h transdermal patch and rivastigmine 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.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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. Overdose with transdermal rivastigmine patches 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 oral rivastigmine formulations.

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 transdermal rivastigmine 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.