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Figure.  Trends in Use and Costs for Oral, Rectal, and Intravenous Formulations of Acetaminophen Within a Cohort of Pediatric Hospitals, 2010-2017
Trends in Use and Costs for Oral, Rectal, and Intravenous Formulations of Acetaminophen Within a Cohort of Pediatric Hospitals, 2010-2017

Use of the intravenous formulation of acetaminophen has rapidly increased among hospitalized children since its market introduction in 2010. Over the same period, use of the oral formulation has remained stable and use of the rectal formulation has decreased. After accounting for changes in hospital volume and changes in unit cost of intravenous acetaminophen over time, the change in utilization rate of intravenous acetaminophen accounted for 95% of the change in total intravenous acetaminophen costs from 2011 to 2017. Currency is reported in 2017 US dollars.

Table.  Cost of Acetaminophen Formulations
Cost of Acetaminophen Formulations
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Vernacchio  L, Kelly  JP, Kaufman  DW, Mitchell  AA.  Medication use among children <12 years of age in the United States: results from the Slone Survey.  Pediatrics. 2009;124(2):446-454. doi:10.1542/peds.2008-2869PubMedGoogle ScholarCrossref
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Shah  SS, Hall  M, Goodman  DM,  et al.  Off-label drug use in hospitalized children.  Arch Pediatr Adolesc Med. 2007;161(3):282-290. doi:10.1001/archpedi.161.3.282PubMedGoogle ScholarCrossref
3.
Lexicomp online. Wolters Kluwer. https://www.wolterskluwercdi.com/lexicomp-online/. Accessed February 4, 2019.
4.
Rockoff  JD, Silverman  E. Pharmaceutical companies buy rivals’ drugs, then jack up the prices. The Wall Street Journal. April 26, 2015. https://www.wsj.com/articles/pharmaceutical-companies-buy-rivals-drugs-then-jack-up-the-prices-1430096431. Accessed January 24, 2019.
5.
Children’s Hospital Association. Pediatric Health Information System. https://www.childrenshospitals.org/programs-and-services/data-analytics-and-research/pediatric-analytic-solutions/pediatric-health-information-system. Accessed September 29, 2018.
6.
Zhu  A, Benzon  HA, Anderson  TA.  Evidence for the efficacy of systemic opioid-sparing analgesics in pediatric surgical populations: a systematic review.  Anesth Analg. 2017;125(5):1569-1587. doi:10.1213/ANE.0000000000002434PubMedGoogle ScholarCrossref
Research Letter
March 11, 2019

Cost Implications of Escalating Intravenous Acetaminophen Use in Children

Author Affiliations
  • 1Pediatric Therapeutics and Regulatory Science Initiative, Computational Health Informatics Program (CHIP), Boston Children’s Hospital, Boston, Massachusetts
  • 2Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
  • 3Center for Applied Pediatric Quality Analytics, Boston Children's Hospital, Boston, Massachusetts
  • 4Program on Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
  • 5Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts
  • 6Department of Anaesthesiology, Harvard Medical School, Boston, Massachusetts
JAMA Pediatr. 2019;173(5):489-491. doi:10.1001/jamapediatrics.2019.0101

Acetaminophen, approved by the US Food and Drug Administration in 1951, is the most frequently used medication in children in the United States.1,2 In outpatient settings, up to 14% of children are treated with acetaminophen for pain and fever in any given week,1 while among hospitalized children, approximately 40% receive acetaminophen.2 The medication is available in multiple formulations, including a rectal suppository for patients unable to take medications by mouth and, most recently, an intravenous formulation, approved by the US Food and Drug Administration in November 2011.

While oral and rectal formulations of acetaminophen are inexpensive, intravenous acetaminophen costs are substantially higher (Table),3 in part owing to patents covering the manufacturing process and dosing of the intravenous formulation. The price of intravenous acetaminophen also more than doubled in 2014 shortly after its manufacturer was acquired by another company.4 We examined the use of this new formulation since its introduction and costs for acetaminophen among hospitalized children.

Methods

We used the Pediatric Health Information System database to identify patients 18 years or younger discharged from pediatric hospitals across the United States from January 1, 2010, to December 31, 2017. The institutional review board at Boston Children’s Hospital deemed the study exempt from review. Patient consent was also exempt from this study. In 2017, the Pediatric Health Information System contained clinical, administrative, and billing information on more than 824 000 hospitalizations in 49 pediatric hospitals, encompassing 83% of US freestanding children’s hospitals.5 We included information from 34 hospitals with complete data over the study period. For each study year, we determined the total number of hospitalizations associated with at least 1 dose of oral, rectal, or intravenous acetaminophen and the total costs adjusted to 2017 US dollars for each formulation. We also calculated the number of hospital days associated with use of each formulation and the number of days on which a patient received both intravenous acetaminophen and an oral drug other than acetaminophen. We evaluated trends in annual acetaminophen use with linear regression models. Statistical analyses were performed in SAS, version 9.4 (SAS Institute Inc).

Results

Of 4 742 209 pediatric hospitalizations, 2 173 688 (46%) were associated with any use of oral, rectal, or intravenous acetaminophen. Use of the oral formulation remained stable at a yearly mean of 41% of hospitalizations (mean change per year, 0.04%; 95% CI, −0.83% to 0.92%; P = .91), resulting in mean yearly costs of $2.2 million (Figure). Use of the rectal formulation fell from 8% to 5% of hospitalizations during the study period (mean change per year, −0.5%; 95% CI, −0.6% to −0.4%; P < .001) and was associated with mean yearly costs of $226 876. Intravenous acetaminophen use increased to 13% of hospitalizations in 2017 (mean change per year, 2.0%; 95% CI, 1.8%-2.2%; P < .001), when it comprised 20% of hospital days with any acetaminophen use and reached $16.0 million in costs. In 2017, 61% of hospital days with intravenous acetaminophen were associated with use of an oral drug other than acetaminophen. The total costs for acetaminophen use among hospitalized children increased from $2.7 million in 2010 prior to the availability of intravenous acetaminophen to $18.1 million in 2017.

Discussion

Intravenous acetaminophen is now administered in about 1 of every 8 pediatric hospitalizations, with its high price leading to meaningful cost increases for pediatric institutions. While the new formulation has been marketed as an alternative to opioids in managing perioperative pain, pediatric surgical patients receiving intravenous acetaminophen have not experienced reductions in opioid consumption or opioid-related adverse events.6

Our study used a noncomprehensive cohort of US pediatric hospitals and could not ascertain the size of potential cost savings, as we do not have information on the appropriateness or effectiveness of intravenous acetaminophen use during these encounters. However, our data show the financial effect that can result when old drugs are reformulated and protected by patents from direct competition. Given the budget impact of intravenous acetaminophen on pediatric hospitals and the prevalence of concomitant use of intravenous acetaminophen with other oral drugs, evidence-based guidelines for its appropriate use may need to be developed.

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Article Information

Corresponding Author: Florence T. Bourgeois, MD, MPH, Boston Children’s Hospital, 300 Longwood Ave, Boston, MA 02115 (florence.bourgeois@childrens.harvard.edu).

Accepted for Publication: October 8, 2018.

Published Online: March 11, 2019. doi:10.1001/jamapediatrics.2019.0101

Author Contributions: Drs Bourgeois and Graham had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Bourgeois, Graham, Randolph.

Critical revision of the manuscript for important intellectual content: Graham, Kesselheim, Randolph.

Statistical analysis: Graham.

Obtained funding: Bourgeois, Kesselheim.

Supervision: Kesselheim, Randolph.

Conflict of Interest Disclosures: Dr Kesselheim reports receiving grants from the US Food and Drug Administration for unrelated work (2013-2016). No other disclosures were reported.

Funding/Support: Dr Bourgeois is supported by the Burroughs Wellcome Fund. Dr Kesselheim’s work is supported by the Laura and John Arnold Foundation and Engelberg Foundation. Drs Bourgeois and Kesselheim are supported by the Harvard-MIT Center for Regulatory Science.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Vernacchio  L, Kelly  JP, Kaufman  DW, Mitchell  AA.  Medication use among children <12 years of age in the United States: results from the Slone Survey.  Pediatrics. 2009;124(2):446-454. doi:10.1542/peds.2008-2869PubMedGoogle ScholarCrossref
2.
Shah  SS, Hall  M, Goodman  DM,  et al.  Off-label drug use in hospitalized children.  Arch Pediatr Adolesc Med. 2007;161(3):282-290. doi:10.1001/archpedi.161.3.282PubMedGoogle ScholarCrossref
3.
Lexicomp online. Wolters Kluwer. https://www.wolterskluwercdi.com/lexicomp-online/. Accessed February 4, 2019.
4.
Rockoff  JD, Silverman  E. Pharmaceutical companies buy rivals’ drugs, then jack up the prices. The Wall Street Journal. April 26, 2015. https://www.wsj.com/articles/pharmaceutical-companies-buy-rivals-drugs-then-jack-up-the-prices-1430096431. Accessed January 24, 2019.
5.
Children’s Hospital Association. Pediatric Health Information System. https://www.childrenshospitals.org/programs-and-services/data-analytics-and-research/pediatric-analytic-solutions/pediatric-health-information-system. Accessed September 29, 2018.
6.
Zhu  A, Benzon  HA, Anderson  TA.  Evidence for the efficacy of systemic opioid-sparing analgesics in pediatric surgical populations: a systematic review.  Anesth Analg. 2017;125(5):1569-1587. doi:10.1213/ANE.0000000000002434PubMedGoogle ScholarCrossref
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