Orthopedics

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Pharmacology Update 

Changing Winds: Practice Implications of Acetaminophen Regulations

Andrew L. Rogalski, PharmD; Kelly M. Smith, PharmD, BCPS, FASHP, FCCP

Abstract

The recommendations garnered from each advisory committee meeting are not binding, and must be evaluated by the FDA executive body before becoming incorporated into official regulations or laws.

The United States Food and Drug Administration (FDA) convened a joint meeting of several of its advisory committees June 29-30, 2009, to discuss recommendations for reducing the incidence of acetaminophen-induced liver injury in American patients. The committee voted in favor of the majority of recommendations presented, and these items will move forward for the FDA to act on. The recommendations address concerns with both over-the-counter (OTC) and prescription products containing acetaminophen, and represent significant changes to product availability and packaging in both arenas. It is essential that practitioners maintain awareness of the changes on the horizon, and that we continue to monitor our patients in our own practices to reduce the incidence of liver injury.

Acetaminophen toxicity occurs when toxic free radicals form in the liver after blood levels exceed the capacity for conversion to nontoxic metabolites. This has been shown to cause potentially fatal acute liver failure when patients are exposed to both high-dose single ingestions such as suicide attempts, as well as chronic ingestion of acetaminophen at doses higher than 4 g/day.1

As noted by the Acute Liver Failure Study Group (ALFSG), the incidence of acute liver failure attributed to acetaminophen in 275 patients increased from 28% in 1998 to 51% in 2003.2 Unintentional overdose accounted for 48% of the study population, while 44% were intentional overdoses or suicide attempts. This high incidence of acute liver failure resulting from unintentional acetaminophen overdose was confirmed by a population based study in 2007.3 Surprisingly, the patients presenting in the ALFSG study with unintentional overdose had no difference in disease severity at onset or 3-week survival. The most common drugs taken by the unintentional overdose group were combination narcotic and acetaminophen products. Concomitant use of alcohol with acetaminophen ingestion has also been shown to increase the extent of liver injury.

Adult dosing limits for acetaminophen in both over-the-counter and prescription products are currently a maximum of 4 g per day. Some studies have examined short-term doses as high as 7 g/day with no evidence of injury, but chronic doses below 4 g/day have been shown to be harmful in some studies.4,5 Pediatric dosing limits are 15 mg/kg per dose with a maximum of 5 doses or 2.6 g in 24 hours.

In the United States, there are currently >100 single ingredient and combination OTC products in various strengths, and a multitude of prescription products, containing acetaminophen primarily in combination with opiate narcotics. Products marketed for pediatric use include concentrated infant drops, syrup formulations, and various chewable tablets. Table 1 includes a sample listing of these products and their varying strengths.

Due to concerns about increasing rates of acetaminophen hepatotoxicity, the FDA commissioned a working group within the Center for Drug Evaluation and Research (CDER) to recommend interventions that would reduce the incidence of acetaminophen induced liver injury.

To further examine possible interventions, in June 2009 the FDA held a joint meeting of 3 of its advisory committees: the Drug Safety and Risk Management Advisory Committee, the Anesthetic and Life Support Drugs Advisory Committee, and the Nonprescription Drugs Advisory Committee.6

As a provision of the Federal Advisory Committee act, the FDA has the authority and ability to commission advisory committees.7 There are currently 48 FDA advisory committees, 16 of which relate specifically to drugs.

The FDA commissions its advisory committees for expert guidance on scientific, technical, and policy topics. These advisory committees meet to discuss specific topics assigned by the FDA, and offer their…

The recommendations garnered from each advisory committee meeting are not binding, and must be evaluated by the FDA executive body before becoming incorporated into official regulations or laws.

The United States Food and Drug Administration (FDA) convened a joint meeting of several of its advisory committees June 29-30, 2009, to discuss recommendations for reducing the incidence of acetaminophen-induced liver injury in American patients. The committee voted in favor of the majority of recommendations presented, and these items will move forward for the FDA to act on. The recommendations address concerns with both over-the-counter (OTC) and prescription products containing acetaminophen, and represent significant changes to product availability and packaging in both arenas. It is essential that practitioners maintain awareness of the changes on the horizon, and that we continue to monitor our patients in our own practices to reduce the incidence of liver injury.

Cause for Concern

Acetaminophen toxicity occurs when toxic free radicals form in the liver after blood levels exceed the capacity for conversion to nontoxic metabolites. This has been shown to cause potentially fatal acute liver failure when patients are exposed to both high-dose single ingestions such as suicide attempts, as well as chronic ingestion of acetaminophen at doses higher than 4 g/day.1

As noted by the Acute Liver Failure Study Group (ALFSG), the incidence of acute liver failure attributed to acetaminophen in 275 patients increased from 28% in 1998 to 51% in 2003.2 Unintentional overdose accounted for 48% of the study population, while 44% were intentional overdoses or suicide attempts. This high incidence of acute liver failure resulting from unintentional acetaminophen overdose was confirmed by a population based study in 2007.3 Surprisingly, the patients presenting in the ALFSG study with unintentional overdose had no difference in disease severity at onset or 3-week survival. The most common drugs taken by the unintentional overdose group were combination narcotic and acetaminophen products. Concomitant use of alcohol with acetaminophen ingestion has also been shown to increase the extent of liver injury.

Adult dosing limits for acetaminophen in both over-the-counter and prescription products are currently a maximum of 4 g per day. Some studies have examined short-term doses as high as 7 g/day with no evidence of injury, but chronic doses below 4 g/day have been shown to be harmful in some studies.4,5 Pediatric dosing limits are 15 mg/kg per dose with a maximum of 5 doses or 2.6 g in 24 hours.

In the United States, there are currently >100 single ingredient and combination OTC products in various strengths, and a multitude of prescription products, containing acetaminophen primarily in combination with opiate narcotics. Products marketed for pediatric use include concentrated infant drops, syrup formulations, and various chewable tablets. Table 1 includes a sample listing of these products and their varying strengths.

Table 1: Commonly Available Single-Ingredient Nonprescription Acetaminophen Products

The FDA Advisory Committee Process

Due to concerns about increasing rates of acetaminophen hepatotoxicity, the FDA commissioned a working group within the Center for Drug Evaluation and Research (CDER) to recommend interventions that would reduce the incidence of acetaminophen induced liver injury.

To further examine possible interventions, in June 2009 the FDA held a joint meeting of 3 of its advisory committees: the Drug Safety and Risk Management Advisory Committee, the Anesthetic and Life Support Drugs Advisory Committee, and the Nonprescription Drugs Advisory Committee.6

As a provision of the Federal Advisory Committee act, the FDA has the authority and ability to commission advisory committees.7 There are currently 48 FDA advisory committees, 16 of which relate specifically to drugs.

The FDA commissions its advisory committees for expert guidance on scientific, technical, and policy topics. These advisory committees meet to discuss specific topics assigned by the FDA, and offer their expertise in providing recommendations for action. These meetings are mandated to be public events, and specific topics are assigned to be discussed. The recommendations garnered from each meeting are not binding, and must be evaluated by the FDA executive body before becoming incorporated into official regulations or laws.

Previous FDA Actions

There is a long history of proposed and actual regulatory, labeling, and product changes based on FDA Advisory Committees. As research began to show that acetaminophen was a major cause of liver injury in the United States, the FDA began to enact regulations to reduce the incidence of overdosage.8

In 1998, the FDA mandated the inclusion of a warning about concomitant use of alcohol on packages of acetaminophen products. In 2002, an Advisory Committee recommended combination product labeling be clarified to note acetaminophen contents. As of 2009, these recommendations have not yet been officially adopted. Their recommendations encouraged regulations to require the inclusion of the word acetaminophen on the face of OTC product labeling.9 They also expressed concern for the multiple pediatric dosage forms available. Further, the committee recommended that manufacturers and the FDA increase educational efforts on the potential dangers of acetaminophen overdose.

In 2004, the FDA began an educational campaign involving advertising and acetaminophen information on the FDA website.6 Advertising efforts were modest due to budgetary constraints, and private venues were reportedly hesitant to run advertising where acetaminophen products were marketed. The FDA also sent a letter to Boards of Pharmacy in every state.10

The letter encouraged individual boards to adopt specific rules to clarify labeling on prescription containers for acetaminophen containing products. They requested the avoidance of the abbreviation APAP on patient prescription labels, which is an abbreviation of the drug’s chemical name n-acetyl-para-aminophenol commonly used by pharmacists and prescribers. They also recommended requiring specific precautions regarding dosing, alcohol use, and use of other acetaminophen products to be dispensed with prescriptions. The National Association of Boards of Pharmacy reported to the FDA in 2008 that no state board had adopted these recommendations.4

In 2006 the FDA recommended changes to OTC product labeling to make it easier to recognize the inclusion of acetaminophen as an ingredient.11 These regulations were finalized on April 29, 2009, and manufacturers were given 1 year to comply with the new requirements.

In 2007, the Center for Drug Evaluation and Research convened a working group to review possible interventions the FDA could enact to address the issue of acetaminophen induced liver injury. The working group developed an extensive report and specific recommendations to the FDA, many of which originated from discussions during the 2002 committee meeting.12 These recommendations and their supporting data were the impetus for the public committee meeting during June 2009.

2009 Advisory Committee Deliberations

Several groups provided briefing documents to be reviewed and discussed during the June joint committee session, including the Rocky Mountain Poison and Drug Center, Consumer Healthcare Products Association (CHPA), Ortho-McNeil Pharmaceuticals, and Johnson & Johnson Pharmaceutical Research and Development.6

The 37 voting members, including physicians, pharmacists, several allied health professionals, and a patient representative, deliberated 9 key concepts posed by the Center for Drug Evaluation and Research working group.13 Of the questions presented, 6 entailed changes to OTC product labeling and availability, 4 of which were supported by the committee. The primary concept reduced the daily maximum dose for OTC acetaminophen products. Acetaminophen is relatively unique in that current maximum OTC dosing recommendations are also the maximum safe dosage for prescription use. Other OTC analgesics, such as NSAIDS, carry a maximum OTC dose lower than maximum safe prescription doses. 4 The committee also favored allowing only 1 formulation of liquid acetaminophen for OTC use. This recommendation stems from the current availability of multiple pediatric dosage strengths, which has been observed to cause confusion among caregivers and unintentional overdoses in pediatric patients.

The advisory group was not in favor of 2 recommendations proposed for OTC products. The majority felt that OTC acetaminophen products were valuable agents on the US market and should continue to be sold. Lastly, the committee voted against a proposal to limit package sizes for OTC products. The United Kingdom implemented similar regulations in 1998, and data to date have not clearly shown a decrease in rates of acetaminophen overdose.5

All 3 recommendations related to prescription acetaminophen combination products received favorable votes by the majority of the committee. They voted distinctly in favor of placing a black box warning on the labeling of prescription products containing acetaminophen. They also favored a provision requiring unit-of-use packaging for prescription acetaminophen products. Current packaging standards allow for the use of the abbreviation APAP when repackaged for dispensing to patients, which is unclear to many. Toxicity warnings are limited, and current practice embeds them within general patient information packets with each prescription. Unit-of-use packaging allows the manufacturer to provide more thorough labeling on a package that is dispensed directly to patients.

Most notably, the group favored discontinuation of all prescription combination acetaminophen products by a vote of 20 to 17. Several agencies and organizations cited concerns that despite the human body’s ability to develop tolerance to the narcotic components of these products, the liver does not develop a tolerance to the acetaminophen component as patients increase dosages. Of the patients presenting with unintentional overdosages in the ALFSG study, 63% were taking a prescription narcotic/acetaminophen combination product.2 However, these narcotic combinations are integral to pain control for many patients and practitioners.

Practice Implications

The FDA has renewed its ongoing interest in addressing acetaminophen toxicity. It is likely that many of the recommendations discussed at the June meeting will be implemented, but there currently is no established timetable or final ruling on each recommendation.

Changes to OTC products are already underway, and will make packaging more understandable to consumers. Many patients are unaware that the OTC and prescription products they use contain acetaminophen, especially those that contain combinations of agents.14

The new recommendations will likely result in changes to suggested dosing to attempt to add a margin of safety between OTC recommended dosing and maximum safe dosing. While these changes will help, we are reminded of how crucial it is that providers interview patients regarding the use of OTC products and account for the amounts of acetaminophen taken. This becomes increasingly important when issuing prescription medications that also contain acetaminophen.

If the FDA adopts the recommendations for OTC products, the new warnings and changes to availability will likely generate questions and concerns from patients. As practitioners we can prepare for these changes by adapting recommendations for OTC acetaminophen use to dosage forms and strengths available, for example adjusting recommendations for parents administering liquid pediatric formulations if a single standard concentration is adopted.

The changes on the horizon for prescription acetaminophen-containing products could change practice immensely. The Consumer Healthcare Products Association reported that hydrocodone/acetaminophen combination products have been the highest volume prescription products dispensed for several years. 4 Furthermore, they are the mainstay of many postoperative and chronic pain regimens. If the FDA accepts the committee recommendation to remove these and other combination products from the market, manufacturers will have to adjust for the shift in demand for single agent narcotics, and practitioners will have to decide how to adapt their prescribing practices as well.

These adaptations will need to account for the available dosage forms that remain available, and may require drastic changes to existing pain regimens for patients who use combination products for chronic pain conditions. If unit-of-use packaging is required, prescription quantities will have to be adapted to avoid confusion during dispensing.

It is also important to note that hydrocodone and all other single agent narcotics used for pain control are Schedule II controlled substances under the US Controlled Substance Act, while component combination products are currently Schedule III and IV (Table 2).

Table 2: Select Acetaminophen-Containing Combination Prescription Products

Schedule II products are not allowed refills and require hard-copy prescriptions for each dispensing, while the Schedule III and IV products are allowed refills in most states. This would represent a major shift in the workload for practitioners involved in the care of chronic pain conditions.

The potential for single-agent narcotic diversion and misuse may also increase. Practitioners may also be hesitant to increase their prescribing of Schedule II products for fear of causing greater scrutiny of their prescribing practices. Prescribers need to plan workflow and policy changes if the decision is made to change patients to schedule II products for pain control.

These proposed changes are aimed at reducing the exposure of patients to dangerous doses of acetaminophen. However, we do not have to wait until new regulatory actions are taken to increase patient safety in regards to acetaminophen overdose. Clinicians should diligently avoid prescribing adult daily doses of acetaminophen in excess of 4 g. For example, a prescription for “Hydrocodone/acetaminophen 5/500 mg, 1 to 2 tablets every 4 to 6 hours” permits patients to take up to 6g of acetaminophen daily.

Patient lack of knowledge about which products contain acetaminophen and appropriate dosing has been identified as contributing to unintentional overdosage.2 Education about product selection and use should occur frequently, especially in patients receiving a combination prescription product. Counseling and medication histories should screen thoroughly for the use of OTC acetaminophen as well, and appropriate use should be encouraged at every opportunity. Such an opportunity is imminent as cold and flu season arrives, and the corresponding increase in likelihood that patients consume OTC symptom relief products that contain acetaminophen.

Many professional organizations have published news stories, electronic feeds, and public statements regarding the proposals and will be resources for practitioners to remain informed. The FDA.gov website currently hosts a front-page link to acetaminophen information that will be useful for both patients and providers. Using these news sources to keep abreast of changes to available products as the FDA acts on the proposed recommendations will ensure consistency of care for our patients.

The Bottom Line
  • The FDA is expected to enact changes to the availability and packaging of both prescription and OTC acetaminophen products to reduce incidence of acetaminophen injury due to overdose.
  • Keeping informed about changes as they arise will ensure continuity of care for patients.
  • Monitoring patients for OTC and prescription acetaminophen usage should be ongoing, and daily adult dosages should not exceed 4 g.

References

  1. Black M. Acetaminophen hepatotoxicity. Annu Rev Med. 1984; 35:577-593.
  2. Holubek WJ, Kalman S, Hoffman RS. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2006; 43(4):880; author reply 882.
  3. Bower WA, Johns M, Margolis HS, Williams IT, Bell BP. Population-based surveillance for acute liver failure. Am J Gastroenterol. 2007; 102(11):2459-2463.
  4. Consumer Healthcare Products Association. Briefing Book: Joint Meeting of the Drug Safety and Risk Management Advisory Committee NDAC, and the Anesthetic and Life Support Drugs Advisory Committee. Washington, DC: Consumer Healthcare Products Association; 2009.
  5. Dart RC, Heard KJ. Comments on liver injury related to the use of acetaminophen. Denver, CO: Rocky Mountain Poison and Drug Center; 2009.
  6. Food and Drug Administration. Briefing Information for the June 29-30, 2009 Joint Meeting of the Drug Safety and Risk Management Advisory Committee with the Anesthetic and Life Support Drugs Advisory Committee and the Nonprescription Drugs Advisory Committee. Available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm161515.htm. Accessed August 1, 2009.
  7. Food and Drug Administration. About Advisory Committees: Laws, Regulations & Guidance. Available at http://www.fda.gov/AdvisoryCommittees/AboutAdvisoryCommittees/LawsRegulationsGuidance/default.htm. Accessed August 1, 2009.
  8. Schiodt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997; 337(16):1112-1117.
  9. Center for Drug Evaluation and Research. Meeting Transcript: Nonprescription Drugs Advisory Committee meeting on safety issues related to acetaminophen. Silver Spring, MD: Food and Drug Administration; 2002.
  10. Food and Drug Administration Center for Drug Evaluation and Research. Acetaminophen hepatotoxicity and nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal and renal toxicity. US Food and Drug Administration Web site. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM171903.pdf. Published January 22, 2004. Accessed August 1, 2009.
  11. Food and Drug Administration Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the Counter Human Use: Proposed Amendment of the Tentative Final Monograph: Required Warnings and Other Labeling, 71 FR 77314-52. Silver Spring, MD: Food and Drug Administration; 2006.
  12. Governale LSI. The Acetaminophen Hepatotoxicity Working Group Recommendations for FDA Interventions to Decrease the Occurrence of Acetaminophen Hepatotoxicity. Silver Spring, MD: Food and Drug Administration; 2008.
  13. Food and Drug Administration. Joint Meeting of the Drug Safety and Risk Management Advisory Committee, Nonprescription Drugs Advisory Committee, and the Anesthetic and Life Support Drugs Advisory Committee: Questions to the Committee. Silver Spring, MD: Food and Drug Administration; 2009.
  14. Stumpf JL, Skyles AJ, Alaniz C, Erickson SR. Knowledge of appropriate acetaminophen doses and potential toxicities in an adult clinic population. J Am Pharm Assoc (2003). 2007; 47(1):35-41.

Authors

Dr Rogalski is from University of Kentucky Healthcare and Dr Smith is from University of Kentucky College of Pharmacy, Lexington, Kentucky.

Drs Rogalski and Smith have no relevant financial relationships to disclose.

Correspondence should be addressed to: Andrew L. Rogalski, PharmD, UK HealthCare, 800 Rose St, H110, Lexington, KY 40536.

doi: 10.3928/01477447-20090818-17

10.3928/01477447-20090818-17

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