Summary Safety Review - Acetaminophen - Liver Injury

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: 2015-07-09

issue

Acetaminophen has been widely used for over 50 years in Canada to treat pain and fever and, when taken as directed, is a safe and effective medicine. Despite its established safety profile, acetaminophen is the leading cause of acute liver failure in Canada. Incidents of serious liver injury associated with acetaminophen continue to be reported in Canada and internationally. The effects of acetaminophen on the liver have been recognized for many years and, over the past 10 years, Health Canada has taken a number of measures to act on information related to the safety of acetaminophen.

In 2009, an initial safety review was conducted by Health Canada in response to a request for stronger label warnings to reduce the occurrence of unintentional acetaminophen overdoses. Following this review, a guidance document, the Acetaminophen Labelling Standard, was released in 2009 to update labelling language for non-prescription acetaminophen products. The new standard included increased warnings for potentially serious and possibly fatal liver injury in the event of an acetaminophen overdose associated with these products.

As part of Health Canada's efforts to minimize health risk factors to Canadians, a more in-depth scientific review was undertaken to evaluate additional evidence and evaluate the situation in Canada. Acetaminophen Overdose and Liver Injury in the Canadian Context (2014) (henceforth referred to as the Acetaminophen Report) contains key findings and recommends options for consideration to further reduce the risk of liver injury to Canadians using acetaminophen.

Background

All medications, including acetaminophen, carry risks. Canada and a number of other countries around the world have taken steps in the past to enable the safe use of acetaminophen and continue to work to address this complex problem. Health Canada has identified options to reduce the risk of liver injury related to acetaminophen in the Acetaminophen Report, and continues to assess the feasibility of which options would be most beneficial in the Canadian context.

Authorized use of acetaminophen in Canada

Prescription and non-prescription acetaminophen products have a long history of treating pain and fever, and their use in Canada dates back to 1961. Acetaminophen is available as a single-ingredient product or in combination with other ingredients, such as in cold and cough medications or narcotic pain relievers (e.g., in combination with codeine). More than 475 different acetaminophen products are authorized for marketing, the majority being non-prescription. Currently, 4 g of acetaminophen per day is the maximum recommended daily dose in Canada and many other countries, while the maximum recommended duration of use is 5 days for pain relief and 3 days for fever.

Acetaminophen overdose and liver injury

Although generally considered to be a safe medicine when taken as directed, taking too much acetaminophen (i.e., more than indicated on the label), either intentionally or unintentionally (both called an overdose), can cause serious liver injury, including acute liver failure. Acute liver failure is a medical emergency and hospitalization is needed right away. It may also result in the need for liver transplantation, or in the most serious of cases, death.

It is generally recognized that doses above 10 g per day in adults (or 150 mg acetaminophen per kg body weight per day) are damaging to the liver. However, there have also been rare reports of liver injury in adults at doses below the maximum recommended dose, mostly in patients with conditions affecting their liver. There is evidence suggesting that the risk of liver injury with acetaminophen use may be increased in certain situations, such as alcoholism, malnutrition, some liver diseases, or use of acetaminophen for more than the recommended length of time.

Canadian context

Health Canada has taken a number of steps to investigate and reduce the risk of liver injury associated with acetaminophen. Two advisories regarding the safe use of acetaminophen have been issued by Health Canada; one in February 2003 and the other in January 2011. In addition, an initial safety review on acetaminophen-induced liver injury was completed in 2009. Health Canada published the Acetaminophen Labelling Standard1 in November 2009, which included improved warnings for the potential for serious and possibly fatal liver injury in the event of an overdose, as well as weight and age-based dosing guidelines for pediatric use. The 2009 safety review also recommended the creation of a Health Canada inter-directorate working group to further study the risk of acetaminophen-induced liver injury. These activities are in line with work done by other countries worldwide.

Objective

The objective of the Acetaminophen Report was to assess the risk of acetaminophen-related liver injury in Canada. Evidence from several sources was considered, including published scientific and medical literature, regulatory-specific documents, case reports of adverse drug reactions sent to Health Canada, data from Canadian hospitals and coroners' offices, and consumer information polls. This information was used to better understand the Canadian context and propose ways to further reduce liver injuries.

Key findings

Use of acetaminophen in Canada2

  • Over 4 billion doses of acetaminophen (e.g., pills) are sold each year in Canada. Approximately 15% of these sales are prescription products.
  • Combination products (acetaminophen plus another medication), including over-the-counter (OTC) cough and cold remedies and pain relievers containing narcotics, account for more than half of all acetaminophen doses sold.

Canadian and scientific reports of overdose, liver injury and hospitalizations associated with acetaminophen

Acetaminophen and overdose

The Acetaminophen Report found that there are more than 4,000 hospitalizations in Canada each year for acetaminophen overdose. Approximately 1 in 5 cases are due to people exceeding the recommended dose unintentionally. An important finding was that the number of hospitalizations for unintentional overdoses is rising in Canada.

Adolescents and young adults were the most likely age group to overdose (both intentionally and unintentionally) with acetaminophen products. It also found overdoses to be more common in females compared to males. The number of cases of overdose leading to liver injury is higher with prescription combination products (i.e., acetaminophen with narcotics) because of their tendency to be used for prolonged periods of time or misused/abused.

Acetaminophen and liver injury

Acetaminophen is the leading cause of all serious liver injury, including acute liver failure, in many countries, such as Canada, the United States, the United Kingdom and Australia. The Acetaminophen Report found that out of the more than 250 cases of serious liver injury per year in Canada related to acetaminophen, over half were associated with unintentional overdoses. This implies that the likelihood of severe liver injuries is more common with unintentional overdoses than intentional overdoses. Most of these cases involved single-ingredient acetaminophen products or prescription combination products containing narcotics.

Moreover, up to 1 in 5 of acetaminophen-related liver injuries reported to Canada Vigilance mentioned doses within the recommended range (i.e., less than 4 g per day - which is equivalent to 8 tablets of extra-strength acetaminophen 500 mg). In many of these cases, patients had identifiable risk factors for acetaminophen liver injury, such as alcoholism or viral liver disease.

Conclusions and actions

  • Although acetaminophen remains a safe and effective medicine, there are risks of serious liver injury when it is not used as directed, such as exceeding the recommended dose or duration of use. Increasing awareness about the presence of acetaminophen in certain medicines and the risk of liver injury when acetaminophen is not used as directed on product labels may help to decrease the occurrence of unintentional overdoses that may cause serious liver injury.

    The 2014 Acetaminophen Report proposes several options for consideration that may reduce the occurrence of acetaminophen-related liver injury, particularly in the context of unintentional overdoses. They include limiting the overall availability of acetaminophen to consumers; lowering the maximum recommended daily dose; decreasing the amount of acetaminophen contained in some products; decreasing the quantity available in a package of acetaminophen; and re-evaluating the role of products that combine both acetaminophen and narcotics. Specific measures for enhancing the safe use in children are also recommended, such as requiring that accurate dosing devices come with all children's liquid products.

    Actions Taken by Health Canada after Completing the Acetaminophen Report

    In July 2014, Health Canada held a technical discussion on the Acetaminophen Report and the recommended risk minimization options with various stakeholders, including patient safety groups, pharmacists, retail pharmacies, and industry associations. As a result of this discussion, a steering committee of Health Canada and stakeholder representatives was tasked with developing and implementing an education approach to promote the safe use of acetaminophen. This collaboration has led to the development of key educational messages, which will be shared by stakeholders with the public through various communication channels beginning in Summer 2015. Health Canada will also be using use social media to disseminate these key messages, and a Web page on acetaminophen safety has already been posted on the Healthy Canadians Web site to inform the public. In addition, Health Canada has issued an Information Update to help educate and remind Canadians about the safe use of acetaminophen.

    In October 2014, Health Canada formed an internal group to assess which of the remaining options were most feasible, and will seek external input on those. Health systems, policy, regulatory, and international perspectives were considered to determine the feasibility of the risk minimization options. New information that has appeared since the Acetaminophen Report was completed, along with the actions of other international regulators, predominately those of the United States Food and Drug Administration, have been taken into account during discussions. To reflect these developments, the Acetaminophen Labelling Standard is being revised to help educate consumers about the possible risks associated with the use of acetaminophen.

    Next Steps

    Health Canada is working collaboratively with its stakeholders as the feasibility and anticipated effectiveness of the remaining risk minimization options from the Acetaminophen Report are further analyzed. Decreasing the maximum recommended daily dose for all oral and rectal forms of acetaminophen containing products is being considered, as is decreasing the unit dose for some products. The improvement of product labelling and packaging, including the requirement that all children's liquid products be sold with an accurate dosing device in the package, is also being examined. Once the Acetaminophen Labelling Standard has been updated, it will be Web posted in Summer 2015 to receive stakeholders' comments before being finalized.

    A technical discussion with stakeholders is planned for Fall 2015 to consider the feasibility of the proposed risk minimization options as recommended by the internal group following further analysis. In addition, Health Canada will continue to collaborate with stakeholders to further develop the acetaminophen education approach.

References

  1. Bond GR, Ho M, Woodward RW. Trends in hepatic injury associated with unintentional overdose of paracetamol (Acetaminophen) in products with and without opioid: an analysis using the National Poison Data System of the American Association of Poison Control Centers, 2000-7. Drug Saf 2012;35(2):149-57.
  2. Hornsby LB, Przybylowicz J, Andrus M, Starr J. Survey of physician knowledge and counseling practices regarding acetaminophen. J Patient Saf 2010;6(4):216-20.
  3. Morgan O, Griffiths C, Majeed A. Impact of paracetamol pack size restrictions on poisoning from paracetamol in England and Wales: an observational study. J Public Health (Oxf) 2005;27(1):19-24.
  4. Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42(6):1364-72.
  5. Abdel-Qader DH, Harper L, Cantrill JA,Tully MP. Pharmacists' interventions in prescribing errors at hospital discharge: an observational study in the context of an electronic prescribing system in a UK teaching hospital. Drug Saf 2010;33:1027-44.
  6. Nguyen NT, Vierling JM. Acute liver failure. Curr Opin Organ Transplant2011;16(3):289-96.
  7. Fontana RJ. Acute liver failure including acetaminophen overdose. Med Clin North Am2008;92(4):761-94, viii.
  8. Bretherick AD, Craig DG, Masterton G, et al. Acute liver failure in Scotland between 1992 and 2009; incidence, aetiology and outcome. QJM 2011;104(11):945-56.
  9. Mort JR, Shiyanbola OO, Ndehi LN, Xu Y, Stacy JN. Opioid-paracetamol prescription patterns and liver dysfunction: a retrospective cohort study in a population served by a US health benefits organization. Drug Saf 2011;34(11):1079-88.
  10. Lee WM. Acetaminophen Toxicity: Changing Perceptions on a Social/Medical Issue. Hepatology 2007;46(4):966-70.
  11. Schilling A, Corey R, Leonard M, Eghtesad B. Acetaminophen: old drug, new warnings. Cleve Clin J Med 2010;77(1):19-27.

Footnotes

  1. A non-prescription drug labelling standard was developed for acetaminophen and outlines the permissible conditions of use and labelling requirements, such as dose, intended use, directions, warnings, active ingredients and combinations thereof for the entire class of products.
  2. 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.
  3. 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 Acetaminophen Summary Report.

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