Limited Benefit From FDA Action to Curb Acetaminophen-Related Liver Toxicity, Study Finds
Health Letter, August 2023
By Azza AbuDagga, M.H.A., Ph.D.
The commonly used fever- and pain-relief medication acetaminophen (also known as paracetamol) is available over the counter (OTC) in oral forms (such as pills, capsules or solutions) — mainly as TYLENOL and multiple store-brand generics — and by prescription. It also is a component of many medications — including analgesic combined opioid medications — which are used to treat moderate-to-severe pain, including acetaminophen, caffeine and dihydrocodeine (TREZIX); acetaminophen and hydrocodone (ANEXSIA); and acetaminophen and oxycodone (OXYCET, PERCOCET).
Generally, acetaminophen is considered safe when its recommended dosages and intervals (see Table below for details) are not exceeded. However, taking higher acetaminophen doses (overdose) can damage the liver. In fact, acetaminophen is responsible for one-half of all reported cases of drug-induced liver injury and approximately 20% of liver transplant cases in the United States.[1] Acetylcysteine (ACETADOTE) is an effective antidote for acetaminophen poisoning, ideally when taken in the first eight hours after exposure.[2]
Since 2011, the Food and Drug Administration (FDA) has required the addition of a boxed warning — the most prominent warning it can require — on the labeling of all acetaminophen-containing medications highlighting the potential for severe liver injury with their use.[3]
Because combined acetaminophen medications increase the risk of liver damage from inadvertently taking multiple medications that contain this drug, the FDA also mandated limiting acetaminophen content in combined acetaminophen medications to 325 milligrams (mg) per tablet or other dosage unit (hereafter, the FDA mandate). However, this mandate, which became effective in late March 2014, did not include OTC acetaminophen-alone medications.[4]
A new well-designed observational study examined how well the FDA mandate has affected liver toxicity from acetaminophen medications in the United States.[5] This study was published in the March 7, 2023, issue of the Journal of the American Medical Association (JAMA).
Individual and Maximum Recommended Dosage of Immediate-Release Acetaminophen[6],[7]
| Acetaminophen Dosage | Children | Adults |
|---|---|---|
| Individual recommended dose* | 10 to 15 mg/kilogram (kg) per dose every four to six hours | 325 to 1,000 mg per dose every four to six hours |
| Maximum recommended dose per 24 hours* | 80 mg/kg | 4,000 mg |
*Note: For frail or underweight patients, lower doses or reduced frequency of administration may be appropriate.
Highlights and implications of the JAMA study[8]
The researchers of this study used contemporaneous data from two sources. The first source was the National Inpatient Sample — a retrospective, all-payer, nationally representative database of discharge data from U.S. hospitals. The second source was the Acute Liver Failure Study Group — a large prospective cohort of adult American and Canadian patients with acute liver failure, defined as a severe form of acute liver injury characterized by rapid onset in the absence of underlying cirrhosis, leading to abnormal coagulation.[9]
Using these data, the researchers compared outcomes in patients who took combined acetaminophen–opioid medications with those of patients who took acetaminophen-alone medications prior to and after the implementation of the FDA mandate.
The good news is that there was a significant and persistent decline in the odds of toxicity-related hospitalization and the predicted proportion of acute liver failure cases associated with the use of combined acetaminophen–opioid medications after the implementation of the FDA mandate. Specifically, whereas the odds of toxicity-related hospitalization associated with the use of combined acetaminophen–opioid medications increased by 1% each year prior to the implementation of this mandate (from January 2007 to March 2014), it decreased by 13% each year afterwards (from April 2014 to December 2019). Additionally, the predicted percentage of acute liver failure cases associated with the use of combined acetaminophen–opioid medications declined from 23% one day prior to the implementation of this mandate to 8% by September 2019.
The bad news is that the study outcomes associated with the use of acetaminophen-alone medications, which are more commonly used than combined acetaminophen–opioid medications, worsened over time. Specifically, whereas the odds of toxicity-related hospitalization associated with the use of acetaminophen-alone medications decreased by 4% each year prior to the implementation of this mandate, they increased by 4% each year after the mandate. Additionally, the predicted percentage of acute liver failure cases associated with these medications increased from 27% one day prior to implementation of the FDA mandate to 34% by September 2019.
In conclusion, the FDA mandate to restrict acetaminophen dosage in combined acetaminophen–opioid medications to 325 mg is a step in the right direction. However, had the agency extended this mandate to over-the-counter acetaminophen-alone medications, much more liver toxicity harm could have been averted in the United States from inadvertent overdose of these medications.
Recommendation for safe use of acetaminophen
If you drink alcohol or have a liver disease, talk to your doctor before taking any acetaminophen medication. Carefully read the labeling of all your prescription and OTC medications (including those for allergy, cold, cough, fever, flu and sleeplessness) and check with your doctor or pharmacist to make sure that you do not exceed the recommended maximum daily dose, or the minimum interval between doses, of acetaminophen.
Do not take more than one acetaminophen-containing medication at any time. Also, try to avoid the use of extra-strength acetaminophen (500 mg or higher tablets or other dosage units) to decrease your risk of overdose.
Note that current acetaminophen labeling instructs adults not to take the drug for longer than 10 days.[10] Therefore, talk to your doctor if you need to take the drug for longer periods, such as for osteoarthritis.
Avoid drinking alcohol and prolonged fasting when taking acetaminophen because that can increase the drug’s toxicity to the liver even at recommended doses.
Beware of the symptoms of potential liver toxicity, including pruritus (itchy skin), jaundice (yellowing of the skin or whites of the eyes), dark urine, upper-right-side abdominal tenderness (where your liver is located) and unexplained flu-like symptoms.[11] Sometimes, there may be no immediate signs or symptoms of overdose. Therefore, if you suspect that you are experiencing an overdose or potential liver toxicity from acetaminophen, do not take any more of this medication and call your doctor immediately or contact a Poison Control Center by calling 800-222-1222.[12]
References
[1] Burns MJ, Friedman SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. March 13, 2023.
[2] Chiew AL, Buckley NA. Acetaminophen poisoning. Crit Care Clin. 2021;37(3):543-561.
[3] Food and Drug administration. FDA drug safety communication: Prescription acetaminophen products to be limited to 325 mg per dosage unit; boxed warning will highlight potential for severe liver failure. January 13, 2011. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit. Accessed June 22, 2023.
[4] Food and Drug administration. All manufacturers of prescription combination drug products with more than 325 mg of acetaminophen have discontinued marketing. March 26, 2014. https://www.fda.gov/drugs/information-drug-class/all-manufacturers-prescription-combination-drug-products-more-325-mg-acetaminophen-have-discontinued. Accessed June 22, 2023.
[5] Orandi BJ, McLeod MC, MacLennan PA, et al. Association of FDA mandate limiting acetaminophen (paracetamol) in prescription combination opioid products and subsequent hospitalizations and acute liver failure liver failure. JAMA. 2023;329(9):735-744.
[6] Burns MJ, Friedman SL, Larson AM. Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation. UpToDate. March 13, 2023.
[7] What dose of paracetamol for older people? Drug Ther Bull. 2018;56(6):69-72.
[8] Orandi BJ, McLeod MC, MacLennan PA, et al. Association of FDA mandate limiting acetaminophen (paracetamol) in prescription combination opioid products and subsequent hospitalizations and acute liver failure liver failure. JAMA. 2023;329(9):735-744.
[9] University of Texas Southwestern Research Labs. Acute Liver Failure Study Group: Research. November 10, 2022. https://labs.utsouthwestern.edu/acute-liver-failure-study-group/research. Accessed June 22, 2023.
[10] Johnson & Johnson Consumer Inc. Label: acetaminophen (TYLENOL). March 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=de5c6654-56c5-40d3-a286-f04ed47ac7c8&type=display. Accessed June 22, 2023.
[11] E-alert: New evidence of liver toxicity in healthy adults taking the maximum recommended dose of acetaminophen (TYLENOL). July 14, 2006. https://www.worstpills.org/e-alerts/view/39. Accessed June 22, 2023.
[12] National Capital Poison Center. Get help online or by phone. https://www.poison.org/. Accessed June 22, 2023.