Objective: To determine the effects of 4-week dose escalation on the gastrointestinal (GI) tolerability of the cholinesterase inhibitor (ChE-I) rivastigmine.
Introduction: Rivastigmine is widely used in the treatment of Alzheimer’s disease (AD). It may cause typical ChE-I class-related adverse events mainly involving the GI system (nausea, vomiting). These occur mostly during the dose titration phase and decrease during the maintenance phase. In early AD clinical trials a relatively high incidence of nausea and vomiting was noted with rivastigmine (approximately 5 and 6x greater than the incidence observed in the placebo group, respectively) following fast titration to the maximum tolerated dose (MTD).1,2 Recent data, however, suggests GI tolerability with rivastigmine is improved by using a slower dose escalation schedule (minimum 4-week interval between dose steps).3,4
Methods/results: In a 26-week open-label multicentre study3 enrolling patients with mixed dementia (n=61) rivastigmine was well tolerated using a 4-week dose escalation schedule (1.5 mg bid to 6 mg bid). Due to the open-label design of the study, no comparison of the incidences of nausea and vomiting with placebo is possible. However, comparison with data from early trials1,2 reveals a reduction in the incidence of both nausea (~40%) and vomiting (~50%). Rivastigmine efficacy was confirmed with significant improvements in cognition, behaviour, global function and activities of daily living. A 22-month open-label study4 comparing rivastigmine with cardioaspirin in VaD patients (n=16) also confirmed the good tolerability of a 4-week dose escalation schedule (1.5 mg bid escalated to a maintenance dose of 3 mg bid). In the rivastigmine group initial transitory nausea was observed at a frequency 1.7 times greater than in the cardioaspirin group. There were no reports of vomiting. Rivastigmine 3 mg bid provided significant and sustained improvements in executive function, behaviour and caregiver burden compared with cardioaspirin. In addition, tolerability results will also be presented from a recently-completed double-blind, placebo-controlled rivastigmine study in 218 patients with moderate to severe AD (MMSE scores 5-12; GDS stage 5-6), using slow dose escalation.
Conclusion: A 4-weekly dose escalation schedule with rivastigmine is associated with improved GI tolerability compared with more rapid titration. This is in line with other reports. A usual therapeutic dose of 3 mg bid also appears to be efficacious in VaD patients.
References
1. Corey-Bloom JF, Anand R, Vaech J et al. Int J Geriatr Psychopharmacol 1998; 1: 55-65. 2. Rösler M, Anand R, Cicin-Sain et al. BMJ 1999; 318: 633-40. 3. Rösler M, Klein HE, Ackenheil M. Poster: American College of Neuropsychopharmacology (ACNP), Puerto Rico, 8-12 December 2002. 4. Moretti R, Torre P, Antonello RM et al. J Neurol Sci 2002; 203-204: 141-6. 5. Shua-Haim J, Smith J, Amin S. Slow dose escalation of rivastigmine treatment of agitation in patients with Alzheimer’s disease: an eight month prospective study. Neurbiol Aging 2002; Vol. 23 (1S): pS73.
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