anticholinesterases, ATC code: N06DA03

rivastigmine hydrogen tartrate

Each capsule contains rivastigmine hydrogen tartrate corresponding to rivastigmine 1.5 mg, 3 mg, 4.5 mg or 6 mg. Each ml contains rivastigmine hydrogen tartrate corresponding to rivastigmine base 2.0 mg.

Hard capsules. Exelon 1.5 mg: Off-white to slightly yellow powder in a capsule with yellow cap and yellow body, with red imprint “Exelon 1.5 mg” on body. Exelon 3 mg: Off-white to slightly yellow powder in a capsule with orange cap and orange body, with red imprint “Exelon 3 mg” on body. Exelon 4.5 mg: Off-white to slightly yellow powder in a capsule with red cap and red body, with white imprint “Exelon 4.5 mg” on body. Exelon 6 mg: Off-white to slightly yellow powder in a capsule with red cap and orange body, with red imprint “Exelon 6 mg” on body. Oral solution. Clear, yellow solution.

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

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.

Rivastigmine should be administered twice a day, with morning and evening meals. The capsules should be swallowed whole. The prescribed amount of solution should be withdrawn from the container using the oral dosing syringe supplied. Rivastigmine oral solution may be swallowed directly from the syringe. Rivastigmine oral solution and rivastigmine capsules may be interchanged at equal doses.

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.

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

Re-initiation of therapy

If treatment is interrupted for more than several 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 adverse reactions.

Patients with severe hepatic impairment have not been studied.

Children

Rivastigmine is not recommended for use in children.

Rivastigmine is not recommended for use in children.

The use of this medicinal product is contraindicated in patients with hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation.

The incidence and severity of adverse reactions generally increase with higher doses. If treatment is interrupted for more than several days, it should be re-initiated at 1.5 mg twice daily to reduce the possibility of adverse reactions (e.g. vomiting).

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, Exelon has been discontinued.

Gastrointestinal disorders such as nausea, vomiting and diarrhoea are dose-related, and may occur particularly when initiating treatment and/or increasing the dose. 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 Dosage Information must be made. Some cases of severe vomiting were associated with oesophageal rupture. Such events appeared to occur particularly after dose increments or high doses of rivastigmine.

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

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.

One of the excipients in Exelon oral solution is sodium benzoate. Benzoic acid is a mild irritant to the skin, eyes and mucous membrane.

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. 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. Patients with severe hepatic impairment have not been studied. However, Exelon 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.

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 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

The most commonly reported adverse reactions 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.

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

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

The following additional adverse reactions have been observed with Exelon transdermal patches: delirium, pyrexia (common).

Table 2 shows the adverse reactions reported in patients with dementia associated with Parkinson's disease treated with Exelon.

Table 2

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

Table 3

Novartis

(POM)

26 January 2012