4.1. Therapeutic indications

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

Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease.

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 or dementia associated with Parkinson's disease. Diagnosis should be made according to current guidelines. Therapy with rivastigmine should only be started if a caregiver is available who will regularly monitor intake of the medicinal product by the patient.

Posology

Initial dose

1.5 mg twice a day.

Dose titration

The starting dose is 1.5 mg twice a day. If this dose is well tolerated after a minimum of two weeks of treatment, the dose may be increased to 3 mg twice a day. Subsequent increases to 4.5 mg and then 6 mg twice a day should also be based on good tolerability of the current dose and may be considered after a minimum of two weeks of treatment at that dose level.

If adverse reactions (e.g. nausea, vomiting, abdominal pain or loss of appetite), weight decrease or worsening of extrapyramidal symptoms (e.g. tremor) in patients with dementia associated with Parkinson's disease are observed during treatment, these may respond to omitting one or more doses. If adverse reactions persist, the daily dose should be temporarily reduced to the previous well-tolerated dose or the treatment may be discontinued.

Maintenance dose

The effective dose is 3 to 6 mg twice a day; to achieve maximum therapeutic benefit patients should be maintained on their highest well tolerated dose. The recommended maximum daily dose is 6 mg twice a day.

Maintenance treatment can be continued for as long as a therapeutic benefit for the patient exists. Therefore, the clinical benefit of rivastigmine should be reassessed on a regular basis, especially for patients treated at doses less than 3 mg twice a day. If after 3 months of maintenance dose treatment the patient's rate of decline in dementia symptoms is not altered favourably, the treatment should be discontinued. Discontinuation should also be considered when evidence of a therapeutic effect is no longer present.

Individual response to rivastigmine cannot be predicted. However, a greater treatment effect was seen in Parkinson's disease patients with moderate dementia. Similarly a larger effect was observed in Parkinson's disease patients with visual hallucinations (see section 5.1).

Treatment effect has not been studied in placebo-controlled trials beyond 6 months.

Re-initiation of therapy

If treatment is interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily. Dose titration should then be carried out as described above.

Renal and hepatic impairment

No dose adjustment is necessary for patients with mild to moderate renal or hepatic impairment. However, due to increased exposure in these populations dosing recommendations to titrate according to individual tolerability should be closely followed as patients with clinically significant renal or hepatic impairment might experience more dose dependent adverse reactions. Patients with severe hepatic impairment have not been studied, however Rivastigmine capsules may be used in this patient population provided close monitoring is exercised (see section 4.4 and 5.2).

Paediatric population

There is no relevant use of rivastigmine in the paediatric population in the treatment of Alzheimer's disease.

Method of administration

Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole.

4.3. Contraindications

The use of this medicinal product is contraindicated in patients with:

- Hypersensitivity to the active substance, or to any of the excipients listed in section 6.1 or other carbamate derivatives.

- 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 higher doses. If treatment is interrupted for more than three days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).

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 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).

Patients and caregivers should be instructed accordingly.

Dose titration: Adverse reactions (e.g. hypertension and hallucinations in patients with Alzheimer's dementia and worsening of extrapyramidal symptoms, in particular tremor, in patients with dementia associated with Parkinson's disease) have been observed shortly after dose increase. They may respond to a dose reduction. In other cases, rivastigmine has been discontinued (see section 4.8).

Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose related, and may occur particularly 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. Cholinesterase inhibitors, including rivastigmine, have been associated with weight loss in these patients. During therapy patient's weight should be monitored.

In case of severe vomiting associated with rivastigmine treatment, appropriate dose adjustments as recommended in section 4.2 must be made. Some cases of severe vomiting were associated with oesophageal rupture (see section 4.8). Such events appeared to occur particularly after dose increments or high doses of rivastigmine.

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).

Care must be taken when using rivastigmine in patients with sick sinus syndrome or conduction defects (sino-atrial block, atrio-ventricular block) (see section 4.8).

Rivastigmine may cause increased gastric acid secretions. Care should be exercised in treating patients with active gastric or duodenal ulcers or patients predisposed to these conditions.

Cholinesterase inhibitors should be prescribed with care to patients with a history of asthma or obstructive pulmonary disease.

Cholinomimetics may induce or exacerbate urinary obstruction and seizures. Caution is recommended in treating patients predisposed to such diseases.

The use of rivastigmine in patients with severe dementia of Alzheimer's disease or associated with Parkinson's disease, other types of dementia or other types of memory impairment (e.g. age-related cognitive decline) has not been investigated and therefore use in these patient populations is not recommended.

Like other cholinomimetics, rivastigmine may exacerbate or induce extrapyramidal symptoms. Worsening (including bradykinesia, dyskinesia, gait abnormality) and an increased incidence or severity of tremor have been observed in patients with dementia associated with Parkinson's disease (see section 4.8). These events led to the discontinuation of rivastigmine in some cases (e.g. discontinuations due to tremor 1.7% on rivastigmine vs. 0% on placebo). Clinical monitoring is recommended for these adverse reactions.

Special populations

Patients with clinically significant renal or hepatic impairment might experience more adverse reactions (see sections 4.2 and 5.2). Dosing recommendations to titrate according to individual tolerability must be closely followed. Patients with severe hepatic impairment have not been studied. However, rivastigmine may be used in this patient population and close monitoring is necessary.

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

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

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 and 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, pilocarpine).

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, halofantrine, mizolastine, methadone, pentamidine and moxifloxacin should be observed with caution and clinical monitoring (ECG) may also be required.

No pharmacokinetic interaction was observed between 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 rivastigmine. No untoward effects on cardiac conduction were observed following concomitant administration of digoxin and rivastigmine.

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 into 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 machinery. Furthermore, rivastigmine can induce dizziness and somnolence, mainly when initiating treatment or increasing the dose. As a consequence, rivastigmine has minor or moderate influence on the ability to drive and use machines. Therefore, the ability of patients with dementia on rivastigmine to continue driving or operating complex machines should be routinely evaluated by the treating physician.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions (ADRs) are gastrointestinal, including nausea (38%) and vomiting (23%), especially during titration. Female patients in clinical studies were found to be more susceptible than male patients to gastrointestinal adverse reactions and weight loss.

Tabulated list of adverse reactions

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).

The following adverse reactions, listed below in Table 1, have been accumulated in patients with Alzheimer's dementia treated with rivastigmine.

Table 1

Infections and infestations

Very rare

Urinary infection

Metabolism and nutrition disorders

Very common

Anorexia

Common

Decreased appetite

Not known

Dehydration

Psychiatric disorders

Common

Nightmares

Common

Agitation

Common

Confusion

Common

Anxiety

Uncommon

Insomnia

Uncommon

Depression

Very rare

Hallucinations

Not known

Aggression, restlessness

Nervous system disorders

Very common

Dizziness

Common

Headache

Common

Somnolence

Common

Tremor

Uncommon

Syncope

Rare

Seizures

Very rare

Extrapyramidal symptoms (including worsening of Parkinson's disease)

Not known

Pleurothotonus (Pisa syndrome)

Cardiac disorders

Rare

Angina pectoris

Very rare

Cardiac arrhythmia (e.g. bradycardia, atrio-ventricular block, atrial fibrillation and tachycardia)

Not known

Sick sinus syndrome

Vascular disorders

Very rare

Hypertension

Gastrointestinal disorders

Very common

Nausea

Very common

Vomiting

Very common

Diarrhoea

Common

Abdominal pain and dyspepsia

Rare

Gastric and duodenal ulcers

Very rare

Gastrointestinal haemorrhage

Very rare

Pancreatitis

Not known

Some cases of severe vomiting were associated with oesophageal rupture (see section 4.4).

Hepatobiliary disorders

Uncommon

Elevated liver function tests

Not known

Hepatitis

Skin and subcutaneous tissue disorders

Common

Hyperhydrosis

Rare

Rash

Not known

Pruritus, allergic dermatitis (disseminated)

General disorders and administration site conditions

Common

Fatigue and asthenia

Common

Malaise

Uncommon

Fall

Investigations

Common

Weight loss

The following additional adverse reactions have been observed with rivastigmine transdermal patches: delirium, pyrexia, decreased appetite, urinary incontinence (common), psychomotor hyperactivity (uncommon), erythema, urticaria, vesicles, allergic dermatitis (not known).

Table 2 shows the adverse reactions reported during clinical studies conducted in patients with dementia associated with Parkinson's disease treated with rivastigmine capsules.

Table 2

Metabolism and nutrition disorders

Common

Decreased appetite

Common

Dehydration

Psychiatric disorders

Common

Insomnia

Common

Anxiety

Common

Restlessness

Common

Hallucination, visual

Common

Depression

Not known

Aggression

Nervous system disorders

Very common

Tremor

Common

Dizziness

Common

Somnolence

Common

Headache

Common

Worsening of Parkinson's disease

Common

Bradykinesia

Common

Dyskinesia

Common

Hypokinesia

Common

Cogwheel rigidity

Uncommon

Dystonia

Not known

Pleurothotonus (Pisa syndrome)

Cardiac disorders

Common

Bradycardia

Uncommon

Atrial Fibrillation

Uncommon

Atrioventricular block

Not known

Sick sinus syndrome

Vascular disorders

Common

Hypertension

Uncommon

Hypotension

Gastrointestinal disorders

Very common

Nausea

Very common

Vomiting

Common

Diarrhoea

Common

Abdominal pain and dyspepsia

Common

Salivary hypersecretion

Hepatobiliary disorders

Not known

Hepatitis

Skin and subcutaneous tissue disorders

Common

Hyperhydrosis

Not known

Allergic dermatitis (disseminated)

General disorders and administration site conditions

Very common

Fall

Common

Fatigue and asthenia

Common

Gait disturbance

Common

Parkinson gait

The following additional adverse reaction has been observed in a study of patients with dementia associated with Parkinson's disease treated with rivastigmine transdermal patches: agitation (common).

Table 3 lists the number and percentage of patients from the specific 24-week clinical study conducted with rivastigmine in patients with dementia associated with Parkinson's disease with pre-defined adverse events that may reflect worsening of Parkinsonian symptoms.

Table 3

Pre-defined adverse events that may reflect worsening of Parkinsonian symptoms in patients with dementia associated with Parkinson's disease

Rivastigmine

n (%)

Placebo

n (%)

Total patients studied

362 (100)

179 (100)

Total patients with pre-defined AE(s)

99 (27.3)

28 (15.6)

Tremor

37 (10.2)

7 (3.9)

Fall

21 (5.8)

11 (6.1)

Parkinson's disease (worsening)

12 (3.3)

2 (1.1)

Salivary hypersecretion

5 (1.4)

0

Dyskinesia

5 (1.4)

1 (0.6)

Parkinsonism

8 (2.2)

1 (0.6)

Hypokinesia

1 (0.3)

0

Movement disorder

1 (0.3)

0

Bradykinesia

9 (2.5)

3 (1.7)

Dystonia

3 (0.8)

1 (0.6)

Gait abnormality

5 (1.4)

0

Muscle rigidity

1 (0.3)

0

Balance disorder

3 (0.8)

2 (1.1)

Musculoskeletal stiffness

3 (0.8)

0

Rigors

1 (0.3)

0

Motor dysfunction

1 (0.3)

0

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 Website (www.mhra.gov.uk/yellowcard).

4.9. Overdose

Symptoms

Most cases of accidental overdose 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.

Treatment

As rivastigmine has a plasma half-life of about 1 hour and a duration of acetylcholinesterase inhibition of about 9 hours, it is recommended that in cases of asymptomatic overdose no further dose of rivastigmine should be administered 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.