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What are the new regulations for acetaminophen mandated by the Food and Drug Administration (FDA)?

Acetaminophen (Tylenol) is a widely used over-the counter (OTC) and prescription medication for fever reduction and pain relief.¹ The drug is generally considered safe with minimal adverse effects when administered appropriately (i.e. daily dosage not to exceed 4 grams). Daily doses greater than 4 grams may result in liver toxicity. During the late 1990s, acetaminophen overdose became the most common cause of acute liver failure (ALF) in the United States (US), surpassing hepatitis B infection, and the incidence of acetaminophen-induced hepatotoxicity continues to increase.^1,2 Since 1998, the Food and Drug Administration (FDA) has been trying to reduce acetaminophen-induced hepatotoxicity through a variety of means including adding an alcohol warning to OTC acetaminophen labeling, creating educational programs, and obtaining assistance from state boards of pharmacy.² Recently, the FDA issued stricter regulations regarding acetaminophen labeling in an effort to reduce the ever increasing prevalence of acetaminophen-related liver injury (Table 1). This summary will provide an overview of acetaminophen-induced ALF and the new regulations issued by the FDA.

The threshold dose for acetaminophen-induced hepatotoxicity leading to ALF is 10 to 15 g for adults and 150 mg/kg for children.¹ After ingestion of toxic amounts of acetaminophen, liver damage can develop due to metabolite accumulation, mitochondrial dysfunction, and alteration of innate immunity. Approximately 90% of acetaminophen is metabolized in the liver by glucuronyltransferases and sulfotransferases, and excreted into the urine. The remaining 10% undergoes metabolism by cytochrome P450 enzymes, particularly 2E1, to a toxic metabolite N-acetyl-p-benzoquinonimine (NAPQI). Excessive amounts of acetaminophen result in the saturation of glucuronyltransferase and sulfotranferase enzymes and accumulation of NAPQI. As a highly reactive molecule, NAPQI forms covalent bonds with proteins, which alter cellular structure and function. The formation of covalent bonds also alters mitochondrial permeability and adenosine triphosphate (ATP) synthesis thus disrupting mitochondrial function and causing cellular necrosis. In addition, the immune system responds to the cellular damage by activating inflammatory mediators (cytokines, natural killer cells, and Kupffer cells), which exacerbate hepatic injury.

As previously mentioned, the incidence of acetaminophen-induced ALF has been increasing over the recent past.³ From January 1998 to December 2003, a prospective study was conducted to determine the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary medical centers in the US. A total of 662 patients meeting the entry ALF criteria (international normalized ratio (INR) ≥1.5, presence of hepatic encephalopathy, and presented within 26 weeks of illness onset with no chronic liver disease) were enrolled in the study. Patients were assessed as having acetaminophen-induced ALF based on the following criteria: history of ingesting >4 g/day of acetaminophen within 7 days of presentation, detection of acetaminophen in serum, or a serum alanine transferase (ALT) level >1000 IU/L. Patients with acute hepatitis A and B, hepatic ischemia, autoimmune hepatitis, Wilson disease, and other etiologies were excluded from the study.

Of the 662 patients with ALF enrolled in the study, 275 (42%) patients fulfilled the criteria for a diagnosis of acetaminophen-induced ALF and were included in the final study group.³ The authors noted an increase in the percentage of acetaminophen-induced ALF cases from 28% in 1998 to 51% in 2003. Unintentional overdose was the most common reason for acetaminophen overdose. There were 131 (48%) patients who reported unintentional overdose compared to 122 (44%) patients who intentionally took an overdose and 22 (8%) patients with an unclear reason for overdose. Patients in the unintentional group were older (median age 38 years), used multiple acetaminophen-containing products frequently (38%), and were less likely to report depression (24%). These results differed significantly when compared to patients in the intentional overdose group: median age 32 years (p=0.002); 5% (p<0.0001); and 45% (p=0.001), respectively for age, products, and depression. Out of 275 patients, 120 (44%) patients reported using narcotic/acetaminophen products with many of the patients being in the unintentional group (63% vs. 18%; p<0.0001). In addition, patients in the unintentional group were more likely to have severe hepatic encephalopathy (grades 3 or 4) on admission compared to the intentional group of patients, (55% vs. 39%; p=0.002). There was no significant difference between the 2 groups with regard to history of past substance abuse and educational level.

Similar results were found in a population-based surveillance for ALF conducted at liver transplant centers and community hospitals in Georgia Health District 3 from November 2000 to October 2004.⁴ Acetaminophen was the most common cause of ALF in adults with more patients (55%) reporting unintentional overdose compared to 45% of patients reporting intentional overdose. The median plasma level of acetaminophen taken prior to hospitalization was 9 to 14 g in patients who unintentionally overdosed. For children, acetaminophen was the second leading cause of ALF with all cases being unintentional. The median plasma level of acetaminophen found in children prior to hospitalization was 3.5 to 5.5 g.

As stated prior, the FDA has tried to increase awareness of acetaminophen-induced hepatotoxicity since 1998.² The most recent action undertaken by the FDA in this regard was more stringent labeling changes for OTC products containing acetaminophen, which are summarized in Table 1.

In addition, the FDA plans to revamp its education programs about acetaminophen and liver damage for consumers and healthcare providers.² The Center for Drug Evaluation and Research suggested ways to reduce acetaminophen overdose and related injuries including:

These suggestions will be evaluated by the FDA, and a decision will be made on which option(s) to implement. For additional information on the new regulations and the proposed recommendations regarding acetaminophen, visit http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009-4429b1-01-FDA.pdf.

As pharmacists, we are in an ideal position to educate patients and healthcare providers on the safe use of acetaminophen and ways to reduce overdose and liver injury. Encourage using a lower maximum daily dose of acetaminophen, especially in elderly, heavy drinkers, and those with liver disease. Additionally, educate patients on which combination products contain acetaminophen and discourage the use of multiple products containing acetaminophen.

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