Summary Safety Review - Atypical Antipsychotics - Liver failure
Review decision
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Issued: 2015-01-22
issue
A safety review was initiated to evaluate the currently available information regarding the potential risk of liver failure associated with atypical antipsychotics, a class of drugs that are mainly used to treat schizophrenia, bipolar disorder and depression. This review was prompted by information from the scientific literature that linked one of these drugs (quetiapine) with the risk of liver failure.
Background
Approved use of atypical antipsychotics in Canada
Atypical antipsychotics marketed in Canada include: aripiprazole, asenapine, clozapine, lurasidone, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone. These products have different approved uses, but generally, atypical antipsychotics are used for the treatment of schizophrenia, bipolar disorder and, in some cases, depression.
Liver failure
Liver failure occurs when the liver has been severely damaged and becomes unable to perform its normal functions. Symptoms of liver failure can include jaundice (yellowing of the skin and the whites of eyes), nausea and vomiting, a general sense of feeling unwell, an accumulation of fluid within the abdomen (ascites), a tendency to bruise and bleed easily and mental disorientation or confusion.
Objective
To assess the available evidence concerning the potential risk of liver failure associated with the use of atypical antipsychotics. This review considered Canadian adverse reaction reports, scientific and medical literature, and international safety data, as well as what is known about the use of these products both in Canada and internationally.
Key findings
Use of atypical antipsychotics in Canadaa
Atypical antipsychotics are frequently prescribed drugs. Quetiapine is the most prescribed atypical antipsychotic, with 7,054,492 prescriptions dispensed in 2012. The number of prescriptions dispensed for all atypical antipsychotics has increased from 10,311,586 in 2008 to 14,786,633 in 2012.
Canadian reports of liver failure associated with atypical antipsychotics
At the time of this review, Health Canada had received several reports of liver failure suspected of being associated with atypical antipsychotics (aripiprazole = 2; asenapine = 0; clozapine = 16; lurasidone = 0; olanzapine = 3; paliperidone = 0; quetiapine = 3; risperidone = 2; and ziprasidone = 0). Some of these cases involved a rapid loss of liver function (acute liver failure). Most of the reports did not provide enough information for a thorough analysis.
Scientific reports
This review was first prompted by 4 literature reports describing cases of liver failure associated with quetiapine (Al Mutairi et al, 2012; El Hajj et al, 2004; Li et al, 2010; Naharci et al, 2011).
Three published cases (two international and one Canadian) suggested a probable association between quetiapine and acute liver failure. Two of these cases resulted in patient death.
Overall, the published evidence linking liver failure with the use of other atypical antipsychotics was limited, with the exception of clozapine and olanzapine, where the risk of liver failure is recognized and included in their prescribing information.
International datab
At the time of this review, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (Vigibase) contained a number of reports involving atypical antipsychotics and liver failures (aripiprazole = 15; asenapine = 4; clozapine = 85; lurasidone = 0; olanzapine = 70; paliperidone = 15; quetiapine = 54; risperidone = 34; and ziprasidone = 15).
Conclusions and actions
Atypical antipsychotics are very widely used. A relatively small number of cases of liver failure have been reported in association with these drugs, although cases were serious and sometimes resulted in death. The risk of liver failure is currently included in the prescribing information for clozapine and olanzapine-containing products. With regard to the other atypical antipsychotics, most of the evidence gathered involved quetiapine.
Health Canada has determined that the overall benefits of quetiapine continue to outweigh the risks, when used as recommended but Health Canada has taken the following actions to minimize the risk of liver failure associated with quetiapine:
- In the April 2014 issue of the Canadian Adverse Reaction Newsletter, Health Canada published an article on quetiapine and the risk of acute liver failure.
- The risk of liver failure has been added to the prescribing information of SEROQUEL (quetiapine). Manufacturers of generic versions of quetiapine will also update their prescribing information.
Evidence linking the other 6 atypical antipsychotics (aripiprazole, asenapine, lurasidone, paliperidone, risperidone and ziprasidone) was limited. Health Canada will continue its ongoing monitoring of adverse reaction information involving all other atypical antipsychotics, as it does for all health products, to identify and assess potential harms. Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.
References
- Al Mutairi F, Dwivedi G, Al Ameel T. Fulminant hepatic failure in association with quetiapine: A case report. J Med Case Rep 2012;6(1):418.
- Bawolak MT. Quetiapine and acute liver failure. Can Advers Reaction Newsl2014;24(2):1-2.
- El Hajj I, Sharara AI, Rockey DC. Subfulminant liver failure associated with quetiapine.Eur J Gastroenterol Hepatol 2004;16(12):1415-8.
- Li J, Zhu X, Liu F, et al. Cytokine and autoantibody patterns in acute liver failure. J Immunotoxicol 2010;7(3):157-64.
- Naharci MI, Karadurmus N, Demir O, et al. Fatal hepatotoxicity in an elderly patient receiving low-dose quetiapine. Am J Psychiatry 2011;168(2):212-3.
Footnotes
- IMS utilization data provided by: IMS Health Canada Inc. An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.
- World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.
- This list of references is not intended to be exhaustive. References have been selected as suggestions for further reading and reflect the most current information at the time of the safety review.