People who start taking donepezil have double the risk of admission with rhabdomyolysis within 30 days compared with those starting rivastigmine or galantamine, researchers have found. In their paper,* published today in the Canadian Medical Association Journal, they point out that the absolute risk of developing severe rhabdomyolysis within 30 days of initiating donepezil remains very low.
The study authors explained that in January 2015, Health Canada issued a post-market surveillance warning about a risk of rhabdomyolysis with donepezil use, based on a single case report in Canada and 88 cases internationally; and that in original randomised controlled trials (RCTs) of donepezil, muscle cramps, but not rhabdomyolysis, were a mentioned adverse effect. In February that year, the US Food and Drug Association recommended updated product monographs with a similar warning of rhabdomyolysis; and the European Medicines Agency followed suit in July 2015. They added that there have been no published case reports of rhabdomyolysis associated with rivastigmine or galantamine, also ‘popular’ cholinesterase inhibitors used to manage the symptoms of Alzheimer disease and other dementias.
They pointed out that there is ‘a paucity of literature on this risk’. So, they conducted a population-based retrospective cohort study in Ontario, Canada, from 2002 to 2017, among women and men aged 66 years or older (mean 81.1 years) who had a newly dispensed prescription for donepezil, rivastigmine or galantamine, to compare the relative risks of hospital admission with rhabdomyolysis within 30 days of initiation of those drugs.
They reported that donepezil was associated with a significantly higher risk of hospital admission with rhabdomyolysis within 30 days of initiation compared with rivastigmine or galantamine (88 events in 152,300 patients [0.06%] vs. 16 events in 68,053 patients [0.02%]; weighted odds ratio of 2.21). They added that most hospital admissions with rhabdomyolysis after donepezil use were not severe, and no patient was treated with acute dialysis or mechanical ventilation.
They also noted that they found no evidence that baseline statin use modified the observed association between donepezil versus rivastigmine or galantamine and the risk of rhabdomyolysis.
They commented: “The 30-day incidence of hospital admission with rhabdomyolysis for patients initiated on donepezil was 6 in 10,000 prescriptions (0.06%), or about 1 in every 1,667 prescriptions. … [Even] if one assumed that the diagnostic codes underestimate true incidence by 10-fold, there would still be only one more hospital admission with rhabdomyolysis for every 300 patients initiated on donepezil, compared with other cholinesterase inhibitors.” Nevertheless, they suggest, it would be ‘prudent’ to consider a diagnosis of rhabdomyolysis and measure creatine kinase level if patients on donepezil describe symptoms of muscle cramping.
They concluded that initiating donepezil is associated with a more than doubled 30-day risk of admission to hospital with rhabdomyolysis, compared with initiating rivastigmine or galantamine, and said: “The findings of this population-based cohort study support regulatory agency warnings about the risk of donepezil-induced rhabdomyolysis. Reassuringly, the 30-day incidence of a hospital admission with rhabdomyolysis after initiating donepezil remains low.”
* Fleet JL, McArthur E, Patel A, et al. Risk of rhabdomyolysis with donepezil compared with rivastigmine or galantamine: a population-based cohort study. CMAJ 2019 September 16; 191: E1018-24. doi: 10.1503/cmaj.190337