Rivastigmine

(British Approved Name, US Adopted Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

(British Approved Name Modified, rINNM)

Drug Nomenclature

Adverse Effects, Treatment, and Precautions

As for Donepezil.

Effects on the gastrointestinal tract.

A 67-year-old woman experienced severe vomiting after rivastigmine, in an oral dose of 4.5 mg, was mistakenly reintroduced without the recommended titration phase; the vomiting was so severe that the patient also suffered a rupture of the oesophagus that needed corrective surgery. The authors’ commented that careful dose titration of rivastigmine is necessary even when restarting treatment.

Interactions

As for Neostigmine. See also Antimuscarinics, under Donepezil, for mention of an interaction between rivastigmine and tolterodine.

Pharmacokinetics

Rivastigmine is readily absorbed from the gastrointestinal tract and peak plasma concentrations are reached in about 1 hour after oral doses. Food delays absorption by about 1.5 hours and reduces maximum plasma concentrations. Absorption from transdermal patches is slow and peak plasma concentrations are reached in 10 to 16 hours after applying the first patch; with subsequent patches, peak concentrations are reached in about 8 hours. Exposure to rivastigmine is highest when the patch is applied to the upper back, chest, or upper arm, and about 20 to 30% lower when applied to the abdomen or thigh.

Rivastigmine is about 40% bound to plasma proteins and readily crosses the blood-brain barrier; it is widely distributed throughout the body. Rivastigmine is rapidly and extensively metabolised, primarily by cholinesterase-mediated hydrolysis to the weakly active decarbamylated metabolite. The plasma half-life is about 1 hour after oral doses and about 3 hours after patch removal. After oral use, more than 90% of a dose is excreted in the urine within 24 hours; no unchanged rivastigmine is detected in the urine. Less than 1% of a dose appears in the faeces.

Uses and Administration

Rivastigmine is a carbamate type reversible acetylcho-linesterase inhibitor; it also inhibits butyrylcholineste-rase. Rivastigmine is selective for the CNS and is used for the symptomatic treatment of mild to moderately severe dementia in Alzheimer’s disease (below) and idiopathic Parkinson’s disease (below). It is given orally as the hydrogen tartrate or in transdermal patches as the base. For both routes doses are expressed in terms of the base; 2.4 mg of rivastigmine hydrogen tartrate is equivalent to about 1.5 mg of rivastigmine. An initial oral dose is 1.5 mg given twice daily with food. Thereafter, the dose may be increased according to response and tolerance by increments of 1.5 mg twice daily at intervals of at least 2 weeks to a maximum dose of 6 mg twice daily.

In the United States of America, licensed product information recommends dose increments at intervals of at least 4 weeks when treating dementia associated with Parkinson’s disease. Transdermal patches delivering 4.6 or 9.5 mg of rivastigmine over 24 hours are also available for once-daily application. In the USA, rivastigmine patches may be used for the treatment of dementia in Alzheimer’s disease or Parkinson’s disease; however, in the UK, use is restricted to dementia in Alzheimer’s disease. An initial transdermal dose is 4.6 mg daily; after at least 4 weeks and if well tolerated, the dose should be increased to 9.5 mg daily. Patients already taking oral rivastigmine may be changed to the patches as follows:

• those taking 6 mg daily or less of oral rivastigmine may be switched to patches delivering 4.6 mg over 24 hours
• those taking more than 6 mg daily orally may be switched to patches delivering 9.5 mg over 24 hours

The first patch should be applied on the day following the last oral dose. The patch should be applied to intact skin on the upper or lower back, or on the upper arm or chest; it should not be applied to the abdomen or thigh due to decreased bioavailability. Re-application to the same site should be avoided for 14 days. If treatment with oral or transdermal rivastigmine is interrupted for more than a few days, it should be restarted at the low initial dose, and then increased as described above. Clinical benefit should be reassessed on a regular basis; treatment should be stopped if there is no improvement after 3 months.

Dementia.

Studies and a systematic review indicate that rivastigmine may be of benefit in the management of patients with mild to moderate dementia in Alzheimer’s disease (see Dementia). In the UK, NICE has recommended that its use should be limited to patients with moderate dementia and given under the following conditions:

• treatment should only be started under specialist supervision
• patients who continue on the drug should be reviewed every 6 months
• treatment should only be continued if there was evidence of benefit

In a somewhat controversial decision, NICE considered that rivastigmine could no longer be recommended in the treatment of mild dementia because its cost-effectiveness was questionable; however, it was recommended that those currently taking rivastigmine for mild dementia should continue on therapy until it was considered appropriate to stop.

Rivastigmine given in titrated doses of up to 6 mg twice daily was also found to be well tolerated, and to produce some improvement in behavioural and psychiatric symptoms, in a group of patients with Lewy-body dementia. However, a systematic review that included this study noted that rivastigmine did not have significant benefit in cognitive function compared with placebo; the authors considered that the evidence for its use in such patients was weak and that further trials were needed.

Rivastigmine has also been tried in the treatment of vascular dementia. A systematic review concluded that although there is some evidence of benefit in these patients, available data are inadequate and further trials were warranted before rivastigmine could be recommended.

For the use of rivastigmine in the treatment of dementia in Parkinson’s disease, see below.

Parkinsonism.

Although acetylcholinesterase inhibitors such as rivastigmine may theoretically worsen parkinsonian symptoms, particularly tremor, it has been tried for use in the treatment of drug-induced psychosis in patients with Parkinson’s disease (see Disturbed Behaviour). In 2 large studies, rivastigmine was found to produce some improvement in symptoms of dementia associated with Parkinson’s disease when compared with placebo.

Proprietary Preparations

Argentina: Exelon; Remizeral;

Australia: Exelon;

Austria; Exelon;

Belgium: Exelon;

Brazil: Exelon; Prometax;

Canada: Exelon;

Chile: Exelon; Probrain;

Czech Republic: Exelon; Prometax;

Denmark: Exelon;

Finland: Exelon;

France: Exelon;

Germany; Exelon;

Greece: Exelon; Prometax;

Hong Kong; Exelon;

Hungary: Exelon;

India: Exelon;

Indonesia: Exelon;

Ireland: Exelon;

Israel: Exelon;

Italy: Exelon; Prometax;

Malaysia: Exelon;

Mexico: Exelon;

The Netherlands: Exelon; Prometax;

Norway: Exelon;

New Zealand: Exelon;

Philippines: Exelon;

Poland: Exelon;

Portugal: Exelon; Prometax;

Russia: Exelon;

South Africa: Exelon;

Singapore: Exelon;

Spain: Exelon; Prometax;

Sweden: Exelon;

Switzerland: Exelon;

Thailand: Exelon;

Turkey: Exelon;

United Kingdom (UK): Exelon;

United States of America (US and USA): Exelon;

Venezuela: Exelon.