Feature

FDA encourages physicians to educate patients on acetaminophen formulations to reduce risk of overdose

By Valerie Pratt, MD; Keith Burkhart, MD; and Ruby Mehta, MD

Acetaminophen-related overdose continues to be a leading cause of ED visits and hospitalizations and remains the leading cause of drug-induced acute liver failure in the United States. Physicians who prescribe products that contain acetaminophen have long played a significant role in helping patients avoid “double dosing” acetaminophen by reminding them to read drug labels so they do not inadvertently overdose by using multiple products that contain acetaminophen.

There’s another valuable way in which physicians can help patients reduce their risk from acetaminophen overdose — by helping patients understand and appreciate the difference between acetaminophen immediate-release (IR) and extended-release (ER) formulations.

Acetaminophen ER has been available over-the-counter (OTC) in the U.S. since 1994 and is currently available under the trade names Tylenol 8 HR Arthritis Pain and Tylenol 8 HR Muscle Aches & Pain, as well as store brands and generics. The amount of ER acetaminophen sold in the U.S. may be more than many health care practitioners might estimate. According to an in-house FDA review, sales of single-ingredient OTC acetaminophen ER from U.S. retail stores to consumers represented 4% of the total sales of single-ingredient OTC acetaminophen in 2014 and increased to 12% in 2017. These data suggest an increase in the use of single-ingredient OTC acetaminophen ER in the U.S. and underscore the need for increased awareness of these two similar, but distinctly different formulations.

Reports in the FDA Adverse Events Reporting System (FAERS) indicate it is difficult to distinguish between the use of IR or ER acetaminophen in cases reporting accidental and intentional overdose. There is much ongoing research on this topic. In December 2017, the European Medicines Agency endorsed a recommendation to suspend marketing of paracetamol modified-release products (also known as acetaminophen ER), since the advantages of a longer-acting product did not outweigh the complications of managing an overdose and it was not feasible, across the European Union, to adopt a standardized way to manage overdose for both IR and ER products. These developments make safety issues related to acetaminophen ER a concern for FDA.

Pill bottle knocked over
Acetaminophen-related overdose continues to be a leading cause of ED visits and hospitalizations and remains the leading cause of drug-induced acute liver failure in the United States.
Source: Adobe Stock

Tylenol 8 HR Arthritis Pain and Tylenol 8 HR Muscle Aches & Pain tablets contain 650 mg of active ingredient per tablet, 325 mg of which is immediately released, with the remaining 325 mg being extended-release. The recommended daily dose is two tablets every 8 hours. If taking the maximum daily dose of acetaminophen ER according to the label, a patient may consume up to six tablets, or a total daily dose of 3,900 mg. Since the pharmacokinetics of acetaminophen ER differ from that of the IR formulation, patients using the ER drug who confuse it with the IR product may exceed the ER product’s recommended dosing and unintentionally absorb toxic amounts of drug.

In poison control and ED settings, health care professionals should attempt to determine whether a patient with a suspected overdose took acetaminophen IR or ER. The difference in pharmacokinetics between IR and ER acetaminophen may result in the need for additional acetaminophen concentration monitoring and a longer regimen of the antidote N-acetylcysteine, which is used for mitigation of acetaminophen-overdose-induced liver injury. The Rumack-Matthew nomogram, an important indicator of the need for treatment for acetaminophen overdose, is a reliable tool for single acute ingestions of the IR formulation. However, a single acetaminophen measurement plotted on the nomograph may not identify all patients overdosed with ER preparations who are at risk for hepatotoxicity and require treatment. As stated in the N-acetylcysteine label, the Rumack-Matthew nomogram may underestimate the hepatotoxicity risk in some, such as those with chronic alcoholism or malnutrition; or those using CYP2E1 enzyme-inducing drugs and/or drugs that delay gastric emptying. Patients who ingest a toxic dose of the ER formulation run the risk of not having their acetaminophen toxicity recognized at the first blood level assessment. Knowing whether patients ingested the ER or IR formulation is critical information for ED physicians in managing patients showing signs of acetaminophen overdose and developing an individualized treatment, such as outlined by the American College of Medical Toxicology, in some cases.

Health care professionals who advise patients to take acetaminophen for pain or fever relief may wish to specify use of IR or ER acetaminophen. When taking a medical history, health care professionals can specifically ask patients who report use of acetaminophen which formulation they take. Both settings present a valuable opportunity to help patients understand the important differences between these products. With so many OTC medications available, it is understandable that some consumers are unaware that both acetaminophen IR and ER formulations are sold. Although the 650 mg ER formulation differs from the 325 mg IR and the 500 mg Extra Strength IR preparations, a consumer in pain or overwhelmed by the many analgesic options available may not notice the difference.

Since acetaminophen is an ingredient in a wide array of pain- and fever-relieving products, cold and allergy preparations, and other medications, it is also important to remind consumers to read Drug Fact labels for active ingredient content to avoid an unintentional acetaminophen overdose from multiple sources. Educating patients to read product labels and to appreciate the differences between products is key to consumer safety.

The FDA asks physicians to remember the similarities and differences between acetaminophen IR and ER and to share this information with patients and other health care professionals as appropriate. Much of what we know about acetaminophen in the U.S. has been gained from reports by health care professionals. The FDA reminds physicians to report adverse events to the MedWatch program. This shared information is critical to developing and advancing safety profiles for FDA-approved therapies.

Valerie Pratt, is Deputy Director for Safety in FDA’s Division of Nonprescription Drug Products

Keith Burkhart, is Senior Advisor for Medical Toxicology in FDA’s Division of Applied Regulatory Science

Ruby Mehta, is a Staff Fellow-Medical Officer in FDA’s Division of Gastroenterology and Inborn Error Products.

By Valerie Pratt, MD; Keith Burkhart, MD; and Ruby Mehta, MD

Acetaminophen-related overdose continues to be a leading cause of ED visits and hospitalizations and remains the leading cause of drug-induced acute liver failure in the United States. Physicians who prescribe products that contain acetaminophen have long played a significant role in helping patients avoid “double dosing” acetaminophen by reminding them to read drug labels so they do not inadvertently overdose by using multiple products that contain acetaminophen.

There’s another valuable way in which physicians can help patients reduce their risk from acetaminophen overdose — by helping patients understand and appreciate the difference between acetaminophen immediate-release (IR) and extended-release (ER) formulations.

Acetaminophen ER has been available over-the-counter (OTC) in the U.S. since 1994 and is currently available under the trade names Tylenol 8 HR Arthritis Pain and Tylenol 8 HR Muscle Aches & Pain, as well as store brands and generics. The amount of ER acetaminophen sold in the U.S. may be more than many health care practitioners might estimate. According to an in-house FDA review, sales of single-ingredient OTC acetaminophen ER from U.S. retail stores to consumers represented 4% of the total sales of single-ingredient OTC acetaminophen in 2014 and increased to 12% in 2017. These data suggest an increase in the use of single-ingredient OTC acetaminophen ER in the U.S. and underscore the need for increased awareness of these two similar, but distinctly different formulations.

Reports in the FDA Adverse Events Reporting System (FAERS) indicate it is difficult to distinguish between the use of IR or ER acetaminophen in cases reporting accidental and intentional overdose. There is much ongoing research on this topic. In December 2017, the European Medicines Agency endorsed a recommendation to suspend marketing of paracetamol modified-release products (also known as acetaminophen ER), since the advantages of a longer-acting product did not outweigh the complications of managing an overdose and it was not feasible, across the European Union, to adopt a standardized way to manage overdose for both IR and ER products. These developments make safety issues related to acetaminophen ER a concern for FDA.

Pill bottle knocked over
Acetaminophen-related overdose continues to be a leading cause of ED visits and hospitalizations and remains the leading cause of drug-induced acute liver failure in the United States.
Source: Adobe Stock

Tylenol 8 HR Arthritis Pain and Tylenol 8 HR Muscle Aches & Pain tablets contain 650 mg of active ingredient per tablet, 325 mg of which is immediately released, with the remaining 325 mg being extended-release. The recommended daily dose is two tablets every 8 hours. If taking the maximum daily dose of acetaminophen ER according to the label, a patient may consume up to six tablets, or a total daily dose of 3,900 mg. Since the pharmacokinetics of acetaminophen ER differ from that of the IR formulation, patients using the ER drug who confuse it with the IR product may exceed the ER product’s recommended dosing and unintentionally absorb toxic amounts of drug.

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In poison control and ED settings, health care professionals should attempt to determine whether a patient with a suspected overdose took acetaminophen IR or ER. The difference in pharmacokinetics between IR and ER acetaminophen may result in the need for additional acetaminophen concentration monitoring and a longer regimen of the antidote N-acetylcysteine, which is used for mitigation of acetaminophen-overdose-induced liver injury. The Rumack-Matthew nomogram, an important indicator of the need for treatment for acetaminophen overdose, is a reliable tool for single acute ingestions of the IR formulation. However, a single acetaminophen measurement plotted on the nomograph may not identify all patients overdosed with ER preparations who are at risk for hepatotoxicity and require treatment. As stated in the N-acetylcysteine label, the Rumack-Matthew nomogram may underestimate the hepatotoxicity risk in some, such as those with chronic alcoholism or malnutrition; or those using CYP2E1 enzyme-inducing drugs and/or drugs that delay gastric emptying. Patients who ingest a toxic dose of the ER formulation run the risk of not having their acetaminophen toxicity recognized at the first blood level assessment. Knowing whether patients ingested the ER or IR formulation is critical information for ED physicians in managing patients showing signs of acetaminophen overdose and developing an individualized treatment, such as outlined by the American College of Medical Toxicology, in some cases.

Health care professionals who advise patients to take acetaminophen for pain or fever relief may wish to specify use of IR or ER acetaminophen. When taking a medical history, health care professionals can specifically ask patients who report use of acetaminophen which formulation they take. Both settings present a valuable opportunity to help patients understand the important differences between these products. With so many OTC medications available, it is understandable that some consumers are unaware that both acetaminophen IR and ER formulations are sold. Although the 650 mg ER formulation differs from the 325 mg IR and the 500 mg Extra Strength IR preparations, a consumer in pain or overwhelmed by the many analgesic options available may not notice the difference.

Since acetaminophen is an ingredient in a wide array of pain- and fever-relieving products, cold and allergy preparations, and other medications, it is also important to remind consumers to read Drug Fact labels for active ingredient content to avoid an unintentional acetaminophen overdose from multiple sources. Educating patients to read product labels and to appreciate the differences between products is key to consumer safety.

PAGE BREAK

The FDA asks physicians to remember the similarities and differences between acetaminophen IR and ER and to share this information with patients and other health care professionals as appropriate. Much of what we know about acetaminophen in the U.S. has been gained from reports by health care professionals. The FDA reminds physicians to report adverse events to the MedWatch program. This shared information is critical to developing and advancing safety profiles for FDA-approved therapies.

Valerie Pratt, is Deputy Director for Safety in FDA’s Division of Nonprescription Drug Products

Keith Burkhart, is Senior Advisor for Medical Toxicology in FDA’s Division of Applied Regulatory Science

Ruby Mehta, is a Staff Fellow-Medical Officer in FDA’s Division of Gastroenterology and Inborn Error Products.