Abstract
This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu.
Background
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are both classified as Lewy body dementias. DLB and PDD are caused by the accumulation of protein deposits of alpha-synuclein inside neurons called Lewy bodies. The distinction between DLB and PDD is based on the sequence and timing of when the symptoms of dementia and movement disorders (parkinsonism) occur. DLB is diagnosed when cognitive impairment develops within 1 year of movement difficulties; if movement disorders (parkinsonism) precede cognitive decline by more than 1 year, PDD is diagnosed. DLB accounts for approximately 20% of all patients diagnosed with dementia and has the following common features: cognitive decline, memory impairment, decrease in executive functioning, hallucinations (especially visual), parkinsonism, changes to REM sleep, and neuroleptic sensitivity.1,2 In patients with DLB, the use of neuroleptic medications should be avoided to treat hallucinations because approximately 30% to 50% of patients may experience severe drug sensitivity reactions such as worsening cognition, parkinsonism, sedation, hypotension, and neuroleptic malignant syndrome.3,4 Cholinesterase inhibitors including donepezil, galantamine, and rivastigmine tartrate, which are US Food and Drug Administration (FDA)–approved treatments for Alzheimer's disease, have been utilized to treat the cognitive symptoms of DLB.1,2,5
Patient Population
Adult patients with dementia with Lewy bodies.
Dosage and Duration
Patients should be started on rivastigmine tartrate 1.5 mg twice daily and titrated at 2- to 4-week intervals by 1.5 mg twice-daily increments to a maximum dose of 6 mg twice daily.6,7 The duration of treatment is not known; however, an open-label study reported patients tolerating up to 96 weeks of treatment. 8
Results
Current guidelines recommend the use of rivastigmine for the treatment of DLB based on one placebo-controlled trial.1,2,9 Rivastigmine may be recommended over other cholinesterase inhibitors due to a lack of data for other cholinesterase inhibitors in this disease state. 1 Rivastigmine treatment reduced hallucinations and improved cognition and functioning compared to placebo in the controlled study and compared to baseline in multiple non-controlled studies.1,2,5,6,8–12
Guidelines
DLB Consortium
The DLB Consortium recommends the use of cholinesterase inhibitors, specifically rivastigmine, to treat the neuropsychiatric symptoms of DLB. Rivastigmine reduced hallucinations and improved attention in one placebo-controlled study. Cholinesterase inhibitors may also improve apathy, sleep disorders, and cognitive symptoms of DLB. 1
American Psychiatric Association
The APA recommends cholinesterase inhibitors for patients with DLB (level II—recommended with moderate clinical confidence). Rivastigmine is not recommended over the other cholinesterase inhibitors. However, the APA notes a lack of strong evidence in this area. 2
American Academy of Neurology
The AAN notes the lack of randomized, controlled trials for the treatment of DLB. However, the AAN suggests that cholinesterase inhibitors, such as rivastigmine, may be beneficial for patients with DLB. 9
British Association for Psychopharmacology
The BAP recommends the use of cholinesterase inhibitors for both cognitive and noncognitive symptoms of DLB (level A, type I evidence) based on controlled and noncontrolled studies in patients with DLB and PDD. Cholinesterase inhibitors appear to be especially effective for the treatment of neuropsychiatric symptoms of DLB, such as hallucinations, apathy, anxiety, and sleep disorders. The BAP does not recommend one cholinesterase inhibitor over the others (level B, type II evidence). 5
Controlled Studies
One 20-week, double-blind, randomized, placebo-controlled study evaluated the use of rivastigmine in 120 patients with DLB. Rivastigmine was given to 59 patients, starting with 1.5 mg twice daily then titrating up to a maximum dose of 6 mg twice daily. Almost one-fourth of patients discontinued the study early (18 in the rivastigmine group and 10 in the placebo group). Behavioral symptoms were assessed with the Neuropsychiatric Inventory (NPI). Other symptoms and cognitive function were assessed with Clinical Global Change-Plus (CGC-Plus) and Mini-Mental State Examination (MMSE) scores. Neuropsychiatric and cognitive symptoms improved with rivastigmine treatment, and more patients on rivastigmine had at least 30% improvement on the NPI compared to patients on placebo (63.4% vs 30.0%; P = .001). Improvements on the MMSE and the CGC-Plus favored rivastigmine treatment, but the difference between the 2 treatment groups was not statistically significant. The investigators concluded that rivastigmine treatment resulted in beneficial behavioral effects in patients with DLB. 6
A retrospective analysis of a controlled study that evaluated patients with Alzheimer's disease compared the effects of rivastigmine to donepezil in participants who also had symptoms of DLB. Rivastigmine was more effective than donepezil at improving cognitive function and slowing impairment in patients with possible Lewy body pathology. In patients without symptoms of DLB, rivastigmine provided no additional benefit compared to donepezil. 10
Non-Controlled Studies
In multiple, small, open-label, non-controlled studies, rivastigmine reduced hallucinations, agitation, and other behavioral symptoms. In studies that evaluated cognition and parkinsonian symptoms, these also improved with rivastigmine treatment.8,11 When compared to patients with Alzheimer's disease who were treated with rivastigmine, patients with DLB who received rivastigmine were more likely to have reduction in hallucinations and improvement in anxiety and sleep disorders. 12
Safety
This is a limited safety profile. Refer to package labeling for complete prescribing information (eg, Warnings/Precautions, Adverse Reactions, Drug Interactions).
Adverse events related to rivastigmine therapy include headache, dizziness, hypersalivation, urinary incontinence, gastrointestinal symptoms (diarrhea, nausea, vomiting), and motor abnormalities (gait disturbances, cogwheel rigidity, hypokinesia).
Therapy Considerations
Rivastigmine improved cognitive and neuropsychiatric symptoms in patients with DLB in one small placebo-controlled study. Patients with DLB who were treated with rivastigmine also reported reductions in hallucination and behavioral symptoms in other small, noncontrolled studies. Cholinesterase inhibitors, including rivastigmine, are recommended by guidelines for the treatment of DLB, although strong evidence to support this recommendation is lacking.
References
- 1.McKeith I.G., Dickson D.W., Lowe J. et al.; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB Consortium. Neurology. 2005; 65(12): 1863–1872. [DOI] [PubMed] [Google Scholar]
- 2.American Psychiatric Association. Practice Guideline for the Treatment of Patients with Alzheimer's Disease and Other Dementias. 2nd ed. Arlington, VA: American Psychiatric Association; 2007. psychiatryonline.org/pb/assets/raw/sitewide/practice_guidelines/guidelines/alzheimers.pdf. [PubMed] [Google Scholar]
- 3.Ballard C., Grace J., McKeith I., Holmes C. Neuroleptic sensitivity in dementia with Lewy bodies and Alzheimer's disease. Lancet. 1998; 351: 1032–1033. [DOI] [PubMed] [Google Scholar]
- 4.McKeith I., Fairfairn A. Perry R., Thompson P., Perry E. Neuroleptic sensitivity in patients with senile dementia of Lewy body type. Br Med J. 1992; 305: 673–678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.O'Brien J.T., Burns A.; BAP Dementia Consensus Group. Clinical practice with anti-dementia drugs: A revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 2011; 25(8): 997–1019. [DOI] [PubMed] [Google Scholar]
- 6.McKeith I., Del Ser T., Spano P. et al. Efficacy of rivastigmine in dementia with Lewy bodies: A randomised, double-blind, placebo-controlled international study. Lancet. 2000; 356(9247): 2031–2036. [DOI] [PubMed] [Google Scholar]
- 7.Exelon (rivastigmine tartrate) [prescribing information]. East Hanover, NJ: Novartis Pharmaceutical Corporation; February 2015. [Google Scholar]
- 8.Grace J., Daniel S., Stevens T. et al. Long-term use of rivastigmine in patients with dementia with Lewy bodies: An open-label trial. Int Psychogeriatr. 2001; 13(2): 199–205. [DOI] [PubMed] [Google Scholar]
- 9.Doody R.S., Stevens J.C., Beck C. et al.; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: Management of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001; 56(9): 1154–1166. [DOI] [PubMed] [Google Scholar]
- 10.Touchon J., Bergman H., Bullock R., Rapatz G., Nagel J., Lane R. Response to rivastigmine or donepezil in Alzheimer's patients with symptoms suggestive of concomitant Lewy body pathology. Curr Med Res Opin. 2006; 22(1): 49–59. [DOI] [PubMed] [Google Scholar]
- 11.McKeith I.G., Grace J.B., Walker Z. et al. Rivastigmine in the treatment of dementia with Lewy bodies: Preliminary findings from an open trial. Int J Geriatr Psychiatry. 2000. a; 15(5): 387–392. [DOI] [PubMed] [Google Scholar]
- 12.Rozzini L., Chilovi B.V., Bertoletti E. et al. Cognitive and psychopathologic response to rivastigmine in dementia with Lewy bodies compared to Alzheimer's disease: A case control study. Am J Alzheimers Dis Other Demen. 2007; 22(1): 42–47. [DOI] [PMC free article] [PubMed] [Google Scholar]